ISQBPPresident’smeeting2016–19-22June

Abstract book

2016PRESIDENT’SMEETING

GrandHotelTerminus,Bergen,Norway,19-22June

08Fall

ISQBPPresident’smeeting2016–19-22June

ScientificCommittee

Nathalie Reuter (University of Bergen, Norway) nathalie.reuter@uib.no Bjørn Olav Bransdal (Arctic University Tromsø, Norway) bjorn-olav.brandsdal@uit.no Michele Cascella (University of Oslo, Norway) michele.cascella@kjemi.uio.no

OrganizingCommittee

Pierre Bèdoucha (University of Bergen, Norway) pierre.bedoucha@uib.no Nathalie Reuter (University of Bergen, Norway) nathalie.reuter@uib.no Edvin Fuglebakk (University of Bergen, Norway) edvin.fuglebakk@gmail.com Bojan Krtenic (University of Bergen, Norway) bojan.krtenic@uib.no Lars Skjærven (University of Bergen, Norway) lars.skjarven@uib.no Sandhya Tiwari (Riken, Japan) sandhyatiwari@gmail.com Tom Venken (University of Bergen, Norway) tom.venken@uib.no Qaiser Waheed (University of Bergen, Norway) qaiser.waheed@uib.no

ISQBPPresident’smeeting2016–19-22June

ListofparticipantsLastname Firstname E-mailregulardelegates Basdevant Nathalie nathalie.basdevant@univ-evry.frBedoucha Pierre pierre.bedoucha@uib.noBethune Iain ibethune@epcc.ed.ac.ukBrandsdal BjørnOlav bjorn-olav.brandsdal@uit.noCappel Daniel daniel.cappel@schrodinger.comCascella Michele michele.cascella@kjemi.uio.noColetta Andrea andrea.coletta@chem.au.dkDeng JinxiaNancy jinxianancy.deng@zoetis.comFUCHS Patrick patrick.fuchs@univ-paris-diderot.frFuglebakk Edvin edvin.fuglebakk@gmail.comGaillard Thomas thomas.gaillard@polytechnique.eduGanguly Abir aganguly@kofo.mpg.deGarcia ElsaSanchez esanchez@mpi-muelheim.mpg.deGillet Natacha natacha.gillet@kit.eduHargus Cory cory.hargus@DEShawResearch.comJuulAndersen Ole ole.andersen@bioch.ox.ac.ukKolli HimaBindu h.b.kolli@kjemi.uio.noLankas Filip filip.lankas@vscht.czLavaggi MariaLaura marialavaggi@gmail.comLiedl Klaus Klaus.Liedl@uibk.ac.atLopez Xabier xabier.lopez@ehu.esLønstadBleken Francesca francescal.bleken@sintef.noMerlino Alicia amerlino@fcien.edu.uyMinoux Herve herve.minoux@sanofi.comNam Kwangho kwangho.nam@chem.umu.sePerezDeLucani BiancaCelidet bperez@eng.au.dkReuter Nathalie nathalie.reuter@uib.noReymer Anna anna.reymer@gu.seRichards Nigel RichardsN14@cardiff.ac.ukSacquin-Mora Sophie sacquin@ibpc.frSaenzMendez Patricia sabioncita@gmail.comSkjaerven Lars lars.skjarven@uib.noSokkar Pandian sokkar@kofo.mpg.deSwang Ole ole.swang@sintef.noTiwari Sandhya sandhyatiwari@gmail.comTrylska Joanna joanna@cent.uw.edu.plVanni Stefano vanni@ipmc.cnrs.frVasilakaki Sofia svasilak@chem.uoa.grVenken Tom tom.venken@uib.noVerma Chandra chandra@bii.a-star.edu.sgWaheed Qaiser qaiser.waheed@uib.nostudents Bacle Amelie amelie.bacle@gmail.comBagherpoorHelabad Mahdi mehdi.bpour@gmail.comBore SigbjørnLøland s.l.bore@kjemi.uio.no

ISQBPPresident’smeeting2016–19-22June

Christensen Mikkel mc@inano.au.dkEBERHARDT Jerôme eberhard@igbmc.frGao Chunxia chunxia.gao@chem.gu.seHartono YossaDwi yossa.dwi.hartono@ki.seIvani Ivan ivan.ivani@irbbarcelona.orgIvanov Stefan ivanovs@bii.a-star.edu.sgKoebel Mathew mathew.koebel@stlcop.eduLadefoged LucyKate lucykate@inano.au.dkLIANG Xujun xujun.liang@cea.frMichelarakis Nicholas nicholas.michelarakis@bioch.ox.ac.ukMisiniIgnjatovic Majda majda.misini_ignjatovic@teokem.lu.seOleinikovas Vladimiras uccavol@ucl.ac.ukPanel Nicolas nicolas.panel@polytechnique.eduPeltzer Raphael raphaelpeltzer@googlemail.comSchauperl Michael michael.schauperl@uibk.ac.atSENAC Caroline caroline.senac@upmc.frTubiana Thibault thibault.tubiana@cea.frZeppelin Talia taliazeppelin@chem.au.dkZivanovic Sanja sanja.zivanovic@irbbarcelona.orginvitedspeakers Brooks Charles brookscl@umich.eduCheatham Thomas tec3@utah.eduCojocaru Vlad vlad.cojocaru@mpi-muenster.mpg.deDejaegere Annick annick@igbmc.frDomene Carmen carmen.domene@kcl.ac.ukFilizola Marta marta.filizola@mssm.eduJorgensen William william.jorgensen@yale.eduKhalid Syma S.Khalid@soton.ac.ukLim Carmay carmay@gate.sinica.edu.twMacKerell Alexander alex@outerbanks.umaryland.eduNilsson Lennart Lennart.Nilsson@ki.seOrozco Modesto modesto.orozco@irbbarcelona.orgPettitt Monte mpettitt@utmb.eduPost Carol cbp@purdue.eduWade Rebecca rebecca.wade@h-its.org

ISQBPPresident’smeeting2016–19-22June

Sunday, June 19th

9:50 City Walk (only for registered participants)

13:30 – 15:30 Registration

15:00 Welcome snack

15:20 Meeting opening

Session: Nucleic Acids I - Chair: Tom Cheatham

15:30 Modesto Orozco

Simulating DNA from the electron to the chromosome

16:10 Montgomery Pettitt

DNA confined: Advantages of non-linear behavior

16:50 Coffee break

17:10 Mahdi Bagherpoor Helabad

The role of Protein-DNA interactions in the DNA binding specificity of hormone receptors

17:30 Lennart Nilsson

Triplex forming oligonucleotides and gene therapy

18:10 Vlad Cojocaru

From decoding dynamics to tailoring cooperativity in protein-DNA interactions

19:00 Dinner at Terminus hotel (only for registered participants)

Monday, June 20th

Session: Nucleic Acids II - Chair: Lennart Nilsson

8:30 Thomas E. Cheatham III

Challenges and successes in modeling RNA structure, dynamics and interactions with ions.

9:10 Joanna Trylska

ISQBPPresident’smeeting2016–19-22June

Interactions of aminoglycoside antibiotics with RNA

9:30 Filip Lankas

Modelling allosteric effects in DNA

9:50 Coffee break

Session: protein-lipid interactions - Chair: Michele Cascella

10:10 Carmen Domene

Computational approaches to the molecular thermometers of the human body

10:50 Syma Khalid

Molecular simulations that put the chemical complexity into model bacterial membranes

11:30 Stefano Vanni

Taking advantage of membrane diversity in intracellular trafficking pathways

11:50 Michael Schauperl

Explaining the recognition process of ice binding proteins

11:50-13:30 Lunch Break

Session: ISQBP awards talks - Chair: Alex MacKerell

13:30 Rebecca Wade - ISQBP Award in Computational Biology

In silico prediction of biomolecular recognition

14:30 Marta Filizola - ISQBP Loew Lectureship

New Challenges and Opportunities in G Protein-Coupled Receptor Drug Discovery

15:30 Coffee Break and Poster session

ISQBPPresident’smeeting2016–19-22June

17:40 Recommended departure to Welcome ceremony (by foot)

18:00 Welcome ceremony by the City of Bergen (at the University Aula, Cf. map)

Tuesday, June 21st

Session: Drug design I - Chair: Annick Dejaegere

8:30 William L.Jorgensen

Design and Discovery of Potent Enzyme Inhibitors

9:10 Daniel Cappel

Rigorous Free Energy Calculations Applied to Protein Homology Models

9:30 Elsa Sánchez-Garcia

Supramolecular Ligands as Regulators of Biomolecular Interactions

9:50 Coffee Break

Session: Drug design II - Chair: Bjørn Olav Brandsdal

10:10 Carmay Lim

Using an old drug to target a new drug site

10:50 Sanja Zivanovic

Multi-level strategy for analysis of bioactive drug conformations

11:10 Chandra Verma

Stapled diets: tackling resistance

11:30 ISQBP General Assembly

12:00-13:30 Lunch Break

Session: Methodological Advances I - Chair: William L. Jorgensen

13:30 Alex MacKerell

ISQBPPresident’smeeting2016–19-22June

Overview of the Classical Drude Oscillator Polarizable Force Field for Biomolecules

14:10 Charles L.Brooks III

High-throughput, free energy based ligand discovery and optimization using multi-site λ-dynamics

14:50 Hima Bindu Kolli

Hybrid Particle-Field Approach with Electrostatics for Mesoscale Biomolecular Simulations

15:10 Iain Bethune

Molecular Integration Simulation Toolkit - interfacing novel integrators with Molecular Dynamics codes.

15:30 Coffee Break

18:30 Recommended departure from Grand Hotel Terminus (by foot, Cf. map)

19:00 Boat departure to Cornelius på Holmen, Conference Dinner, sponsored by the Journal of Chemical Theory and Computation (JCTC)

Wednesday, June 22nd

Session: Methodological Advances II – chair: Vlad Cojocaru

8:50 Thomas Gaillard

Computational Protein Design with an MMGBSA Energy Function

9:10 Kwangho Nam

Development and acceleration of multiscale QM/MM methods for simulations of complex biomolecular systems

9:30 Xabier Lopez

ISQBPPresident’smeeting2016–19-22June

Aluminum and bioligand interactions with phosphate containing groups.

9:50 Coffee Break

Session: Enzyme and protein dynamics – chair: Nathalie Reuter

10:10 Annick Dejaegere

Structural dynamics and signalling mechanisms in nuclear retinoid receptors

10:50 Carol Post

An unusual allosteric mechanism for regulating protein interactions of Syk tyrosine kinase

11:30 Natacha Gillet

Understanding Charge Transfer in Cryptochromes and Photolyases via QM/MM Simulations: Application to PhrB Protein

11:50 Thibault Tubiana

Norovirus Capsid Assembly

12:10 Closing remarks

12:30 Lunch

ISQBPPresident’smeeting2016–19-22June

Talks

ISQBPPresident’smeeting2016–19-22June

T1:SimulatingDNAfromtheelectrontothechromosome

M.Orozco*[1,2,3]

[1]InstituteforResearchinBiomedicine(IRBBarcelona),TheBarcelonaInstituteofScienceandTechnology,Barcelona,Spain

[2]JointBSC-IRBResearchPrograminComputationalBiology,Barcelona,Spain

[3]DepartmentofBiochemistryandMolecularBiology,UniversityofBarcelona,Barcelona,Spain

ISQBPPresident’smeeting2016–19-22June

T2:DNAconfined:AdvantagesofNon-linearbehavior

B.M.Pettitt*[1,2,3]

[1]SealyCenterforStructuralBiologyandMolecularBiophysics,UniversityofTexasMedicalBranch(UTMB),USA

[2]DepartmentofPharmacologyandToxicology,UTMB

[3]BiochemistryandMolecularBiology,UTMB

ThenonlinearelasticpropertiesofDNAmoleculesaresensitivetoenvironment.DNAisdoublestrandedandoccasionallyknottedbutmustopentoforreplication,repair,transcriptionandrecombination.Onopeningtheelasticpersistencelengthchangesbyovertwoordersofmagnitude.Thesizeofmanyvirusorphagecapsidsisthesameasthepersistencelengthmakingpackingofperfecthelicesunreasonable.TheinterfacebetweenhardsurfacesorproteinsandnucleicacidschangesthepropertiesofDNA..Interfacesofferlargeelectrostaticfieldsanddensitygradientschangingthelocalfreeenergysurfaceandthereforeformachallengingsetofproblemsincurrentdesignissues.WeshowsimpleanalyticmodelsformeltingtemperatureshiftsinreasonableagreementwithexperimentforbothDNA.Ourcoarsegrainedmodelsdescribeaspectsofsequenceandtargetlengthdependence.Ourdescriptionofphagepackingincludesatomicandcoarsegrainedsimulations.

ISQBPPresident’smeeting2016–19-22June

T3:TheroleofProtein-DNAinteractionsintheDNAbindingspecificityofhormonereceptors

M.BagherpoorHelabad*[1],P.Imhof[2]

[1]DepartmentofPhysics,FreeUniversityofBerlin,Germany

[2]DepartmentofPhysics,FreeUniversityofBerlin,Germany

-HorrmonereceptorssuchastheAndrogen(AR)andGlococorticoid(GR)receptorbindtogenomicresponseelementsandregulategenetranscriptionwithinthecell.Bothreceptorsbindasahomo-dimeronthesameinvertedrepeatelements5–AGAACA–3.However,GRfailstobindtodirectrepeatswhereasARformsstableenoughprotein-(DR)DNAcomplexestoallowcrystallization.Thisdifferentbehavior,whichcanberegardedasacrucialkeyinspecificregulationuponhormonebinding,hasbeendiscussedtooriginateindifferencesintheproteindimerstabilityordimerformationratherthaninprotein-DNAinteraction.Inthelightofthelargesimilarityofthetwohormonereceptorproteinsandtheirsubtledifferencesinspecificityweareexploringwhichfactorsinprotein-DNAinteractionorintheproteinsubunit-subunitinteractionallowthereceptorproteinstorecognizetheirspecificsiteamonganoverwhelmingnumberofnon-specificDNAsequences.Also,neighboringeffectontheDNAhavebeenstudiedtoshowhowflankingsitesareessentialinprotein-DNAinteraction.Wehaveperformedmoleculardynamics(MD)simulationsofdirectandinvertedresponseelementswithandwithoutpresenceofproteinsaswellasGlococorticoidreceptor-DNAsystemswithdifferentflankingbases.Changingtheflankingsitebasesappearstoresultinadifferentrelativepositioningofthedimer-halves.Moreover,hydrogen-bondandcorrelationanalysesshowthatthetworeceptors(ArandGR)interactdifferentlywiththetwohalf-sites.

ISQBPPresident’smeeting2016–19-22June

T4:Triplexformingoligonucleotidesandgenetherapy

L.Nilsson*[1],A.Villa[1],Y.Xu[1],Y.Hartono[1],C.I.E.Smithe[2],K.Lundin[2],V.Pabon[2],R.Zain-Luqman[3]

[1]Dept.Biosci.Nutr.,KarolinskaInstitutet,Sweden

[2]Dept.Lab.Med.,KarolinskaInstitutet,Sweden

[3]Dept.Wom.Child.Health,KarolinskaInstitutet,Sweden

Aneverincreasingnumberofpathologicalconditionshavebeenfoundtohavegeneticcomponents.Sometimesasingledefectivegene(e.g.Huntingtons’s),othertimesmorecomplexmultigenecausesareimplicated.Ifthecauseisanon-functionalgene(i.e.,theproteinproductdoesnotwork)itmighthelptosupplythecellwithagoodcopyofthegeneinquestion–genetherapy.Thereplacementgeneconstructcanbecontainedinaplasmid,whichhastobedeliveredtothenucleus.Bydecoratingtheplasmidinamodularwaywithfunctionalgroups,themachineryalreadypresentinthecellmaybe'hi-jacked'toperformthisdelivery.

Weusesimulationstooptimizethecomposition(includingtheuseofmodifiednucleotides,e.g.LNAornovelbases)andsequenceoftriplexformingoligonucleotides(TFOs)tobindwithhighaffinityandspecificitytodoublestrandedDNAandfunctionasananchorforfunctionalgroupsdecoratingaplasmidcarryinggeneticmaterialtobeintroducedinthenucleus.SystematicfreeenergycalculationsareappliedtosetsofsystemswiththemodifiednucleotidesindifferentpositionsanddifferentsequencecontextsintheTFO.

ISQBPPresident’smeeting2016–19-22June

T5:Fromdecodingdynamicstotailoringcooperativityinprotein-DNAinteractions

V.Cojocaru*[1]

[1]ComputationalStructuralBiologyLaboratory,DepartmentofCellandDevelopmentalBiology,MaxPlanckInstituteforMolecularBiomedicine,Germany

Protein-DNAinteractionsareatthecoreoftranscriptionalregulatorynetworksdefiningcellularidentities.Iwillfocusonoureffortstodescribethedynamicsunderlyingprotein-DNAinteractionsusingatomisticsimulations.Inparticular,IwillpresentourrecentprogressindecipheringdynamicmechanismsofcooperativeDNAbindingbytranscriptionfactorsandhowthesemayimpactoncellfatedecisions.Engineeredtransitionsbetweendifferentcelltypeshaveagreatpotentialtoinfluencefutureregenerativetherapyapproachesandareusuallyinducedbycocktailsofveryfewtranscriptionfactors.Todesignoptimizationstrategiesforsuchcellularprocesses,itiscrucialtounderstandthemechanismsbywhichthetranscriptionfactorsrecognizeDNAfrombothagenomicandanatomisticperspective.Iwillreflectonhowourdataandmolecularsimulationsingeneralmaycontributetothisimportantbiologicalandmedicalproblem.

ISQBPPresident’smeeting2016–19-22June

T6:It'snotallbroken:ChallengesandsuccessesinmodelingRNAstructure,dynamicsandinteractionswithions.

T.Cheatham*[1]

[1]DepartmentofMedicinalChemistry,UniversityofUtah,SaltLakeCity,USA

RNAforcefieldscontinuetoimproveandprovideanaccurateunderstandingofion-dependentconformationalchangesorfolding,yetatthesametimetherearestillseriouslimitations.Wecanexposetheselimitationsbyovercomingsamplingproblemsthroughverylargescaleensemblesimulations.Exposingthelimitationsprovideshintsastohowtoadaptorimprovetheforcefieldaswemovetowardsmethodstomoresystematicallytestandevolvethenucleicacidforcefields.

ISQBPPresident’smeeting2016–19-22June

T7:InteractionsofaminoglycosideantibioticswithRNA

J.Trylska[1]*,

[1]CentreofNewTechnologies,UniversityofWarsaw,Poland

ManyantibioticstargetbacterialribosomalRNAbybindingtoitsfunctionallyimportantsites.Onecrucialsiteisthedecodingsite,whichisalsothebindingsiteforaminoglycosideantibiotics.AminoglycosidebindingdecreasestheaccuracyofdecodingbyaffectingthemobilityoftwoadeninestakingpartintherecognitionofcognatetRNAs.

Iwouldliketodescribeoureffortstounderstand(thermo)dynamicsofaminoglycosiderecognitionbyribosomalRNA.AminoglycosidebindingsiteformsaflexibleRNAbulgeandevensinglepointmutationschangeaminoglycosideaffinities.WeapplymoleculardynamicssimulationstoinvestigatethereasonsfordifferentselectivitiesofaminoglycosidestowardtheirRNAbindingsitesofvariousorganisms.Wealsocomparethebindingmodesofdifferentaminoglycosidestoproposeaminoglycosidemodificationsthatwouldenhancetheiraffinitiesandreducebacterialresistance.

ISQBPPresident’smeeting2016–19-22June

T8:ModellingallostericeffectsinDNA

T.Drsata[1,2],F.Lankas*[1]

[1]InstituteofOrganicChemistryandBiochemistry,AcademyofSciencesoftheCzechRepublic,Prague,CzechRepublic

[2]DepartmentofPhysicalandMacromolecularChemistry,FacultyofScience,CharlesUniversityPrague,CzechRepublic

IthasbeenincreasinglyappreciatedthatallostericeffectstakeplacenotonlyinproteinsbutalsoinDNA.Intherecentyears,severalexperimentalworksinvestigatedDNAallosteryinvolvingsmallmolecules,someofthemprospectivedrugs(1,2)aswellasproteins(3),butaplausibletheoreticalmodelwasmissing.WehaveproposedatheoreticalframeworktodescribeDNAallostery(4,5).OurmodelrepresentstheDNAasalinearelasticsystemincludingintra-basepairandinter-basepaircoordinates,andgroovewidths.Theshapeandstiffnessparametersareinferredfromlarge-scale,atomic-resolutionunrestrainedmoleculardynamicssimulationsofDNAoligomers.Theresultingelasticenergyfunctionthenundergoesconstrainedminimization,withallostericeffectorbindingmimickedbytheconstraints.Theassumptionofquadratic(harmonic)deformationenergyallowsustofindananalyticsolutionfortheminimum.ThemodelhasbeenusedtonearlyquantitativelypredictvariousallostericeffectsinDNAinvolvingsmallmoleculesandproteins(4,5).Wewillbrieflypresentthemodel,discussitsadvantagesandlimitations,andshowsomeofitsapplications.

1.Chenoweth,D.M,Dervan,P.B.(2009):AllostericmodulationofDNAbysmallmolecules.Proc.Natl.Acad.Sci.USA106,13175-13179

2.Tevis,D.S.,...,Wilson,W.D.(2009):Large,sequence-dependenteffectsonDNAconformationbyminorgroovebindingcompounds.NucleicAcidsRes.37,5550-5558

3.Kim,S.etal.(2013):ProbingallosterythroughDNA.Science339,816-819

4.Drsata,T.,...,Lankas,F.(2014).MechanicalmodelofDNAallostery.J.Phys.Chem.Lett.5,3831-3835

5.Drsata,T.,...,Lankas,F.(2016).OntheuseofmoleculardynamicssimulationsforprobingallosterythroughDNA.Biophys.J.110,874-876

ISQBPPresident’smeeting2016–19-22June

T9:Computationalapproachestothemolecularthermometersofthehumanbody

C.Domene*[1]

[1]DepartmentofChemistry,King'sCollegeLondon,UK

Transientreceptorpotential(TRP)ionchannelsconstituteanotablefamilyofcationchannelsinvolvedintheabilityoforganismstodetectnoxiousmechanical,thermalandchemicalstimulithatgivesrisetotheperceptionofpain.OneofthemostexperimentallystudiedagonistofTRPchannelsiscapsaicin,whichisresponsiblefortheburningsensationproducedwhenchilipepperisincontactwithorganictissues.UnderstandinghowTRPchannelsareregulatedbycapsaicinandothernaturalproductsisessentialtohighimpactpharmacologicalapplications,particularlythoserelatedtopaintreatment.Byselectedexamplesfromtheworkwehavecarriedout,Iwillprovideanoverviewofthecurrentknowledgewehaveaboutactivation,permeationandselectivityofoneofthehumanmolecularthermometers.

ISQBPPresident’smeeting2016–19-22June

T10:Molecularsimulationsthatputthechemicalcomplexityintomodelbacterialmembranes

D.Jefferies,P.C.Hsu,J.Graham,S.Khalid*

[1]SchoolofChemistry,UniversityofSouthampton,UnitedKingdom

Allcells,whetherprokaryoticoreukaryotic,areseparatedfromtheexternalenvironmentbyatleastonemembrane.Thesemembranesprovideaphysicalbarriertotheentryofunwantedortoxicsubstancesincludingdrugs,intotheinteriorofthecell.Toenterthecell,drugsmusteitherpermeatethroughthelipidcomponentofthebilayers,orthroughtheproteinsthatareembeddedwithinthemembranes.Thenativemembraneproteinsareestimatedtobethetargetsof>50%ofdrugs.

Somedrugs,includingmanyantibioticsworkbycausingcelllysisthroughdirectdisruptionofthecellmembrane,ratherthanentryintothecell.Thusitisclear,thatunderstandingthecellmembranesofbacteriaareimperativeforthefuture,rationaldesignofnoveldrugs,inparticularantibiotics.IwillpresentresultsofourrecenteffortstosimulatetheinteractionofantimicrobialpeptidesandothermoleculessuchasfullereneswiththemembranesofGram-negativebacteria.Iwillfirstdescribehowwehaveconstructedrealistic,complexmodelsofthemembranesattwodifferentlevelsofresolution,followedbyadiscussionofhowthemodelsarebeingusedtounderstandtheactionofmembrane-activechemicalspecies.Iwillconcludewithadiscussionoffuturedirectionsandpossibilitiesforcollaborationwithexperimentalcolleagues.

ISQBPPresident’smeeting2016–19-22June

T11:Takingadvantageofmembranediversityinintracellulartraffickingpathways

S.Vanni*[1],R.Gautier[1],H.Hisaaki[1],M.Magadelene[1],B.Antonny[1].

[1]InstitutdePharmacologieMoleculaireetCellulaire,CNRS,France

Biologicalmembranesplayanessentialroleinmanycellularsignalingpathways.Yet,becauseofdifficultiesinperformingstructuralstudiesonlipidmembranes,severaloftheirmolecularpropertiesremainelusive,thuspreventingtoestablishclearstructure-functionrelationships.

Toovercometheselimitationsandtoelucidatetheroleofmembranepropertiesindifferenttraffickingpathways,wedevelopedamultidisciplinaryapproachthatcombinesmoleculardynamicssimulationswithexperimentalmeasurementsinvitroandinvivo.

Inthistalk,Iwillpresentourrecenteffortstodevelopnewexperimentalandcomputationalapproachestofurtherpushforwardourunderstandingofcellularmembranesinmolecularterms.

ISQBPPresident’smeeting2016–19-22June

T12:Explainingtherecognitionprocessoficebindingproteins

MichaelSchauperl*[1],KlausR.Liedl[1]

[1]InstituteofGeneral,InorganicandTheoreticalChemistry/TheoreticalChemistryandCenterforMolecularBioscienes(CMBI),UniversityofInnsbruck,Austria

Purewaterfreezesat-37°C,becausetheformationoficeiskineticallyhinderedathighertemperatures.[1]Thecommonknownpropertyofwater,freezingat0°C,resultsonlyfromimpuritiesinthewateractingasicenuclei.Icenucleiaresubstancescatalyzingtheformationofice.Thisphenomenonisespeciallysignificant,whenwaterisfoundinsmalldroplets,asitisintheartificialsnowproductionandtheformationofcloudsintheatmosphere,whereithasahugeimpactontheearth’sclimate.[3]

Experimentalstudiesshowedthatthemostefficientclassofknownicenucleiareproteins.Theseproteinsaretermedicenucleationproteins[2]andcatalyzefreezingofwateralreadyathighertemperatures(0to-5°C).

Themechanismoficenucleationitselfispoorlyunderstood,whenseeninrelationtoitsrelevance.Inourstudiesweinvestigatedtheicenucleationprocessbymoleculardynamicssimulationstogaininsightintheunderlyingprinciple.Thefocusinthisstudywastodescribethehydrationpropertiesofwatermoleculesinthesurroundingoftheprotein.Ourstudyrevealedthaticenucleationisfacilitated,iftheenthalpicinteractionbetweenwaterandtheproteinislow,andincontrast,theentropyofthesurroundingwatermoleculesismediumorhigh.Basedontheseresults,weproposedanewimprovedmechanismfortheicenucleationprocessoficenucleationproteins.

[1]Murray,B.J.etal.E.Chem.Soc.Rev.2012,41,6519-6554.

[2]Pummer,B.G.etal.J.Atmos.Chem.Phys.2015,15,4077-4091.

[3]Morris,C.E.eta.lPhys.IVFrance2004,121,87–103.

ISQBPPresident’smeeting2016–19-22June

T13:Insilicopredictionofbiomolecularrecognition

RebeccaC.Wade*[1,2]

[1]MolecularandCellularModelingGroup,HeidelbergInstituteforTheoreticalStudies(HITS),Heidelberg,Germany

[2]CenterforMolecularBiology(ZMBH)atHeidelbergUniversity,DKFZ-ZMBHAlliance,andInterdisciplinaryCenterforScientificComputing(IWR)Heidelberg,Germany

IwilldescriberecentapplicationsofmolecularmodellingandBrownian[1,2]andmoleculardynamicssimulationmethodstostudyinghowproteinsrecogniseandbindtotheirdiversebindingpartners.Iwilldiscussthepredictionofbothspecificandnon-specificinteractionsbetweenproteinswhilefocusingontheeffectsofmacromolecularcrowding[3],transientinteractionsofchaperoneproteins[4],andallostericregulationofglycolyticenzymes[5].

[1]Martinezetal.J.Comput.Chem.,(2015)36:1631-1645

[2]Yuetal.Nucl.AcidsRes.,(2015)43:W220-W22

[3]Balboetal,Biophys.J.,(2013)104:1576-84.

[4]Nillegodaetal.Nature,(2015)524:247–251

[5]Gdyniaetal,Nat.Commun.(2016)7:10764

ISQBPPresident’smeeting2016–19-22June

T14:NewChallengesandOpportunitiesinGProtein-CoupledReceptorDrugDiscovery

M.Filizola*[1]

[1]DepartmentofStructuralandChemicalBiology,IcahnSchoolofMedicineatMountSinai,NewYork,NY

GProtein-CoupledReceptors(GPCRs)remainoneofthemostpursuedtargetsfordrugdevelopment,andthesubjectoffocusedstudies.However,muchhaschangedintheGPCRfieldsinceIjoinedDr.GildaLoew’sMolecularResearchInstitutefifteenyearsago.Forinstance,high-resolutioncrystalstructuresofGPCRshaveimprovedourperceptionofreceptorbindingandactivation,andhaveestablishednewdirectionsforunderstandingthemolecularmechanismsunderlyingthediversephysiologicalfunctionsmediatedbythesereceptors.Highperformancecomputationalcapabilities,combinedwithefficientlyparallelizedmoleculardynamicscodesand/ormultiscalesystemrepresentations,havealsoimproveddramatically,allowingustoreachtimescalesinmolecularsimulationsthatwereonceconsideredinaccessible.Whiletheseadvancementshavecreatednewopportunitiesforrationaldrugdiscovery,theyhavealsorevealednewchallenges.Takingfulladvantageofbothhigh-resolutioncrystallographicinformationandpowerfulcomputationalresources,mylabhasmostrecentlyfocusedontestingenhanced,moleculardynamics-basedstrategiesinanattempttoovercomethesechallengesandtocontributemechanisticdetailsofGPCRfunctionthatareimpossibleordifficulttoretrieveexperimentally.Iwillprovideafewexamplesoftheseapproachesandtheirresults.

ISQBPPresident’smeeting2016–19-22June

T15:DesignandDiscoveryofPotentEnzymeInhibitors

W.L.Jorgensen*[1]

[1]DepartmentofChemistry,YaleUniversity,USA

Drugdiscoveryisbeingpursuedthroughcomputer-aideddesign,synthesis,biologicalassaying,andcrystallography.LeadidentificationfeaturesdenovodesignwiththeligandgrowingprogramBOMBordockingofcommercialcompoundlibraries.Thefocusofthislecturewillbeoptimizationoftheresultantleadstoyieldpotentinhibitors.Specifically,MonteCarlo/free-energyperturbation(FEP)simulationsareexecutedtoidentifythemostpromisingchoicesforsubstituentsonrings,heterocycles,andlinkinggroups.TheillustratedapplicationscenteronthedesignofinhibitorstargetingHIV-1reversetranscriptaseandmacrophagemigrationinhibitoryfactor.Micromolarleadshavebeenrapidlyadvancedtolownanomolarorpicomolarinhibitors,andnumerouscrystalstructuresfortheprotein-inhibitorcomplexeshavebeenobtained.DevelopmentofafluorescencepolarizationassayforMIFbindingwillalsobepresented.Keyissuesforsuccessareconsideredincludingconfidenceinthestructureofprotein-ligandcomplexes,biologicalassays,forcefields,atomicchargemodels,andconformationalsampling.

DiscoveryandcrystallographyofbicyclicarylaminoazinesaspotentinhibitorsofHIV1reversetranscriptase.Lee,W.-G.;Frey,K.M.;Gallardo-Macias,R.;Spasov,K.A.;Chan,A.H.;Anderson,K.S.;Jorgensen,W.L.Bioorg.Med.Chem.Lett.2015,25,4824-4827.

Design,Synthesis,andProteinCrystallographyofBiaryltriazolesasPotentTautomeraseInhibitorsofMacrophageMigrationInhibitoryFactor.Dziedzic,P.;Cisneros,J.A.;Robertson,M.J.;Hare,A.A.;Danford,N.E.;Baxter,R.H.G.;Jorgensen,W.L.J.Am.Chem.Soc.2015,137,2996-3003.

ISQBPPresident’smeeting2016–19-22June

T16:RigorousFreeEnergyCalculationsAppliedtoProteinHomologyModels

D.Cappel*[1],W.Sherman[2]

[1]SchrödingerGmbH,Dynamostr.13,68259Mannheim,Germany

[2]SchrodingerInc.,120W45thSt.,NewYork,NY10036,USA

Oneofthemostprominentchallengesincomputer-aideddrugdesignisthereliableandaccuratepredictionofprotein-ligandbindingaffinities.Moleculardynamicsbasedfreeenergyperturbation(FEP)calculationsareamongthemostsuitablemethodstoreachthisgoal.RecentadvancementsinsamplingmethodsandforcefieldscoupledwithmoderncomputationalresourcesmakeFEPpracticalinadrugdesigncontext.[1-3]However,previousFEPvalidationworkshavereliedonaccuratecrystalstructures,whichareoftennotavailableindrugdiscoveryprojects.Assuch,theabilitytoapplyFEPonhomologymodelswouldgreatlyexpandthedomainofapplicabilityandvalueofFEPindrugdiscovery.InthisworkweapplytheFEP+procedure[2]oncongenericligandseriesbindingtofourdiversetargets(Tyk2kinase,anepigeneticbromodomaintargetBRD4,atransmembraneGPCRA2A,andBCL-2familyproteinMCL-1)usingcrystalstructuresandhomologymodels.Surprisingly,theperformanceusinghomologymodelsisgood,andgenerallyonaparwiththecrystalstructures.Thiscanbeattributedtothedynamicssimulations,whichallowthemodeledreceptortoadapttothe“real”conformation.

[1]C.D.Christ,T.Fox,JChemInfModel2014,54,108-120.

[2]L.Wang,Y.Wu,Y.Deng,B.Kim,L.Pierce,G.Krilov,D.Lupyan,S.Robinson,M.K.Dahlgren,J.Greenwood,D.L.Romero,C.Masse,J.L.Knight,T.Steinbrecher,T.Beuming,W.Damm,E.Harder,W.Sherman,M.Brewer,R.Wester,M.Murcko,L.Frye,R.Farid,T.Lin,D.L.Mobley,W.L.Jorgensen,B.J.Berne,R.A.Friesner,R.Abel,JAmChemSoc2015,137,2695-2703.

[3]T.B.Steinbrecher,M.Dahlgren,D.Cappel,T.Lin,L.Wang,G.Krilov,R.Abel,R.Friesner,W.Sherman,JournalofChemicalInformationandModeling2015,55,2411-2420

ISQBPPresident’smeeting2016–19-22June

T17:SupramolecularLigandsasRegulatorsofBiomolecularInteractions

S.Mittal[1],K.Bravo-Rodriguez[1],E.Sanchez-Garcia*[1]

[1]DepartmentofTheory,Max-Planck-InstitutfürKohlenforschung,MülheimanderRuhr,Germany

Theinteractionsofproteinswithsmallmoleculescansignificantlyinfluencethefunctionalityofsystemsofdiversestructuralcomplexity.Ouraimistounderstandtheseassociationsinordertodesignmoleculesthatcanmodulateprotein–proteininteractions,amongothers.ThecombinationofMolecularDynamicssimulationswithFreeEnergycalculationsandQM/MMmethodsallowsustopredictligandbindingsitesinaproteinandtoproposeimprovedligandsabletoreachspecificproteinregionsofbiologicalrelevance.

Moleculartweezers(MT)actaspotenthostsforpositivelychargedresidues.ExperimentalstudieshaveshownthatMTarepromisingcandidatesfortheregulationofproteininteractions.(1)Inthiscontext,weinvestigatedthebishydrogenphosphatemoleculartweezerCLR01,withamyloidogenicpeptidestoproposemechanismsfortheinhibitionoftoxicaggregationbymoleculartweezers.(2-3)AsakeysteptowardthedesignofimprovedligandswealsoinvestigatedtheeffectofthesubstituentsintheabilityofMTstointeractwithaminoacidsandsmallpeptides.(4)ThestudyofMTswithproteinhostslike14-3-3adapterproteins,allowedustoestablishgeneralrulesforpredictingtherelativestrengthandtypeofinteractionofthetweezerswithspecificresiduesinproteinsfeaturingseveraltentativebindingsites.(5)Lastbutnotleast,byinvestigatingtheeffectofmoleculartweezersonlipidbilayers,wewereabletoproposeanovelmechanismforviralmembranedisruptionbyasupramolecularligand.

1. J.Am.Chem.Soc.2011,133,16958-16969.

2. ACSChem.Biol.2015,10,1555–1569.

3. elife,2015,4:e05397

4. J.Org.Chem.2013,78,6721-6734.

5. Nat.Chem.2013,5,234-239.

ISQBPPresident’smeeting2016–19-22June

T18:Usinganolddrugtotargetanewdrugsite

Yu-MingLee[1],YulanderDuh[2],Shih-TingWang[2],MichaelM.C.Lai[2]HannaS.Yuan[2]andCarmayLim[1]*

[1]InstituteofBiomedicalSciences,AcademiaSinica,Taipei115,Taiwan

[2]InstituteofMolecularBiology,AcademiaSinica,Taipei115,Taiwan

Inviralproteins,labileZn-sites,whereZn2+iscrucialformaintainingthenativeproteinstructurebuttheZn-boundcysteinesarereactive,arepromisingdrugtargets.Here,weaimto(i)identifylabileZn-sitesinviralproteinsusingguidelinesestablishedfromourpreviousworkand(ii)assessifclinicallysafeZn-ejectingagentscouldejectZn2+fromthepredictedtargetsiteandthusinhibitviralreplication.Asproof-of-concept,weidentifiedalabileZn-siteinthehepatitisCvirus(HCV)NS5Aproteinandshowedthattheanti-alcoholismdrug,disulfiram,couldinhibitHCVreplicationtoasimilarextentastheclinicallyusedantiviralagent,ribavirin.ThediscoveryofanovelviraltargetandanewrolefordisulfiramininhibitingHCVreplicationwillenhancethetherapeuticarmamentariumagainstHCV.ThestrategypresentedcanalsobeappliedtoidentifylabilesitesinotherbacterialorviralproteinsthatcanbetargetedbydisulfiramorotherclinicallysafeZn-ejectors.

ISQBPPresident’smeeting2016–19-22June

T19:Multi-levelstrategyforanalysisofbioactivedrugconformations

S.Zivanovic*[1,2],A.Hospital[1,2],M.Orozco[1,2,3]

[1]InstituteforResearchinBiomedicine(IRBBarcelona),TheBarcelonaInstituteofScienceandTechnology,Barcelona,Spain

[2]JointBSC-IRBResearch,Barcelona,Spain

[3]DepartmentofBiochemistryandMolecularBiology,UniversityofBarcelona,08028Barcelona,Spain

Computer-aideddrugdesign(CADD)isoneofthepowerfultoolswhichcanbeusedtoincreasetheefficiencyofthedrugdiscovery.Estimatingtherelativefreeenergyofaligandinitstarget-boundstate(bioactiveconformation)isnecessarytooptimizethepotencyofbioactivemoleculesandtoimprovetheaccuracyofSDBBmethods.Ouraimistodevelopanefficientframeworkforfindingthebioactiveconformationoftheflexibleligands.Sincethebioactiveconformationoftheligandmaydifferfromtheglobalminimumofthefreeligandinthephysiologicalenvironment,onehastoevaluatetheenergeticcostrequiredforadoptingthebioactiveconformation.Asetof100crystalstructuresofpharmaceuticallyrelevantdrug-likemoleculeswastestedusingmulti-levelapproach.Wecombinedlow-levelmethod(LL)forsamplingtheconformationalminimaandhigh-level(HL)ab-initiocalculationsforestimatingtheirrelativestabilityinordertoexaminetheconformationalspaceofflexibleligandsandtoobtaintherelativefreeenergyoftheconformationalwells.Themethodwasautomatedandtestedonvariousligandswithdifferentnumbersofatoms,chargeandrotatablebonds.ThepreliminaryresultsshowthatitisnecessarytoperformHamiltonianReplicaExchangesimulationsforLLmethodinordertoexploreallpossiblestatesofenergylandscapeofgivendihedrals.Ourfindingssuggestthatthemethodisaneffectivewaytoimproveanalysisofthebioactiveconformationsofdrug-likemolecules.Itisworthnotingthatpresentframeworkformultilevelstrategyisacomplexandlong-termtask,whichrequiresalotofrehearsalsandimplementations.Takingintoaccounttheflexiblenatureofmolecules,protonationstateandtautomericforms,makesourtaskevenmorechallenging.Theproposedstrategymayrepresentanefficienttoolforpredictingtheconformationallandscapeofdrugswhilekeepingareasonablebalancebetweenchemicalaccuracyandcomputationalcost.

ISQBPPresident’smeeting2016–19-22June

T20:Stapleddiets:tacklingresistance

VermaC.*[1]

[1]BioinformaticsInstitute,A*Star,Singapore

Amajorproblemwithcurrentmoleculartherapiesistoxicityandresistanceandovercomingthesehasproventobelargelydifficult.Recentdevelopmentsinunderstanding,technologyandapplicationsofpeptidesasmodulatorsofprotein-proteininteractions,combiningcomputationalandexperimentalmethodshasbeguntoopennewwindowsintotacklingthisproblemandprovidecauseforcautiousoptimism.

ISQBPPresident’smeeting2016–19-22June

T21:OverviewoftheClassicalDrudeOscillatorPolarizableForceFieldforBiomolecules.

A.D.MacKerellJr.*[1]

[1]DepartmentofPharmaceuticalSciences,SchoolofPharmacy,UniversityofMaryland,Baltimore,USA

Explicittreatmentofelectronicpolarizabilityinempiricalforcefieldsoffersthepotentialtosignificantlyimprovetheaccuracyofmolecularsimulationsofmacromoleculesincondensedphases.TowardsachievingthiswehavedevelopedapolarizableforcefieldbasedontheclassicalDrudeoscillatormodel.Importantlythemodeliscomputationallyaccessibleallowingformicrosecondsimulationsofmacromoleculesaswellastheapplicationofenhancedsamplingandfreeenergyperturbationmethodologies.ImprovementsinthemodelovertheadditiveCHARMM36forcefieldonthetreatmentofthecooperativityofhelixformationofthe(AAQAA)3peptide,onbaseflippinginDNAandontheinteractionsofionswithDNAindicatestheutilityofexplicittreatmentofelectronicpolarizabilityinaforcefield.Anoverviewofthemodelwillbepresentedalongwithongoingdevelopmentsintheforcefieldincludingintheareasofnucleicacids,proteinsandcarbohydrates.

ISQBPPresident’smeeting2016–19-22June

T22:High-throughput,freeenergybasedliganddiscoveryandoptimizationusingmulti-siteλ-dynamics

C.L.BrooksIII*[1,2]

[1]DepartmentofChemistry,UniversityofMichigan,USA

[2]DepartmentofBiophysics,UniversityofMichigan,USA

Evaluatingprotein-ligandbindingaffinitiesisacentralproblemincomputationalstatisticalmechanicsofbiologicalmolecules.Whilefreeenergysimulationsarewellestablished,theyarealsohighlycomputationallyintensive,andlimittherangeandscopeofsystemsthatcanbestudied.OverthepastdecadewehavedevelopedanextendedLagrangianapproachtofreeenergysimulationscalledλ-dynamics,andmorerecentlyamulti-siteversionwetermmulti-siteλ-dynamics.Inthisrigorousstatisticalmechanicalframeworkthesystemofinterest“evolves”dynamicallyinthespaceofchemicalsubstituentsofinterestandthussignificantlyenhancestheefficiencyofthesearchproblemandconvergenceoftheoverallfreeenergycalculations.Moreover,withinthisformalism,weintroducebiasesthatrepresentthesolvationcomponentoftherelevantthermodynamiccycle,andtherebydirectlysimulateligandbindingcompetitionexperiments,fromwhichwedirectlyevaluaterelativebindingaffinityforlargefamiliesofligands.IwilldescribetheextendedLagrangianmethodologyandillustrateitinthecontextoflarge-scaleligandscreeningcalculations.Generalizationstopermitbothsequence-basedresistantmutationsandligandaffinitieswillbedescribed.

ISQBPPresident’smeeting2016–19-22June

T23:HybridParticle-FieldApproachwithElectrostaticsforMesoscaleBiomolecularSimulations

HimaB.Kolli*[1],SigbjørnL.Bore[1],AntonioDeNicola[2],GiuseppeMilano[2],MicheleCascella[1]

[1]DepartmentofChemistryandCentreforTheoreticalandComputationalChemistry(CTCC),UniversityofOslo,P.O.Box1033,Blindern,0315Oslo,Norway

[2]DipartimentodiChimica,UniversitàdiSalerno,viaPontedonMelilloFiscianoSalernoI-84084,Italy

Recentdevelopmentsonhybridparticle-fieldapproachwhereMolecularDynamicsiscombinedwithSelfConsistentFieldtheory(MD-SCF)[1]haveproventobeefficientinexploringlargespatialandtemporalscalesforsystemsinthecondensedphaseatmolecularresolution.Unliketypicalcoarsegrain(CG)Hamiltonians,whicharebasedonpairwiseinteractionpotentials,MD-SCFcomputestheenergyofthesystemofinterestasafunctionaloftheparticledensity.Implementationofgridcomputationmethodsallowsquasi-linearscalingandminimaluseofnode-communication,makingMD-SCFsimulationsintrinsicallyfasterthanparticle-basedconventionalapproaches[2].

TheextensionoftheMD-SCFmethodwithexplicittreatmentofelectrostaticinteractionshasbeenintroducedveryrecently[3].Likeindensityfield,thechargedmoleculesareinteractingwiththeexternalchargefieldthatdependsonthedistributionofchargedensities.ThismethodhasbeensuccessfullyimplementedinbothserialandparallelversionsoftheOCCAMcode[4].Thisapproachiscurrentlybeingextendedtothefieldtreatmentofelectrostaticmultipoledensities.Theaccuracyofthemethodistestedforasetofprototypicpolyelectrolytemultiphasesystems,monitoringbothbulkandinterfaceproperties.AnadvantageforbiomolecularsystemsistheintegrationofMD-SCFapproachestoCGmodelsforbiopolymerswhereelectrostaticfeaturesaremappedbytopologicalmultipolarreconstruction[5].Thisproposedapproachisgeneralandcanbeusedtosimulatediversecomplexmultiphasesystems(i.e.polymers,membranes,proteins,nucleicacids)beyondthetime-andlength-scalesaffordabletoday.

[1]G.MilanoandT.Kawakatsu,JChemPhys,130,214106(2009).

[2]A.DeNicolaetal.,JChemTheoryComput,10,5651(2014).

[3]You-LiangZhuetal.,(submitted)

[4]http://www.smms.unisa.it/occam

[5]M.Cascellaetal.,JChemTheoryComput,4,1378(2008);D.Alemanietal.,JChemTheoryComput,6,315(2010).

ISQBPPresident’smeeting2016–19-22June

T24:MolecularIntegrationSimulationToolkit-interfacingnovelintegratorswithMolecularDynamicscodes.

I.Bethune*[1],E.Breitmoser[1],B.J.Leimkuhler[2]

[1]EPCC,TheUniversityofEdinburgh,UK

[2]MaxwellInstituteforMathematicalSciencesandSchoolofMathematics,TheUniversityofEdinburgh,UK

ModernproductionMolecularDynamicscodesrepresentasignificantinvestmentofeffortbythecommunitytodevelophighlyoptimisedforceevaluationroutinesabletotakeadvantageofstate-of-thearthardwaresuchasGPUsandmulti-coreCPUs.However,thiscomesatacostofcodecomplexitywhichmakesithardfornewintegrationalgorithmstobeimplementedinthesepackages.Thiscreatesacatch-22foralgorithmdevelopement-ifnewalgorithmscannotbeimplementedandtestedinproductioncodesitmaybeimpossibletodemonstratetheirbenefitsoverexistingschemes;conversely,ifthecommunitycannotseethebenefitofnewalgorithms,codedeveloperswillnotspenttimeimplementingthem!

TheMolecularIntegrationSimulationToolkit(MIST)libraryisasolutiontothisproblembyprovidingplug-instoexistingoptimisedMDcodes,coupledwithasimpleinterfaceforthedevelopmentofnewintegrationmethods.MISTcurrentlyprovidesinterfacestoGROMACS,AmberandNAMD-Lite,allowingittobenefitfromOpenMPandGPUaccelerationforforce-evaluation.Severalstandard(Verlet,Leapfrog)andnew(LangevinDynamicsbasedonaBAOABsplitting)integratorshavebeenimplementedtodate.TheMISTlibraryinterfaceresultsinsignificantease-of-development,atnegligiblelossofperformance.Newintegrationalgorithmsareimplementedonce,inacode-agnosticmanner,andcanthenbeimmediatelydeployedinalltheMDcodessupportedbyMIST.

Aswellasalgorithmsforsamplingthecanonicalandmicro-canonicalensembles,MISTisalsoaplatformforbuildingmoreadvancedschemes.Forexample,wehaveimplementedanextended-systemmethodfor'ContinuousTempering',whichenablescomputationoffreeenergymapsinsystemswithlargeenergybarriers.

SeveralnewfeaturesareunderdevelopmentinMIST-newconstraintsolversforextremelylongtimestepsandmulti-timestepsplittings,MPIparallelisation,andsupportformoreMDcodes.Wewelcomethecommunity'sinputondirectionforfuturedevelopment.

ISQBPPresident’smeeting2016–19-22June

T25:ComputationalProteinDesignwithanMMGBSAEnergyFunction

T.Gaillard*[1],N.Panel[1],D.Mignon[1],T.Simonson[1]

[1]LaboratoiredeBiochimie,EcolePolytechnique,Palaiseau,France

Proteindesignaimsatconceivingnewproteinsormodifyingexistingonestoobtainagivenfunction.Computationalapproachesareavaluablehelpforproteindesign,torationalizethepredictionsandguidetheexperimentaltests.Computationalproteindesign(CPD)hassparkedimportantmethodologicaleffortsandobtainedspectacularsuccessessuchasthecreationofaproteinwithanewfoldorenzymeactivesiteengineering.ThemaindifficultyofCPDliesintheastronomicalnumberofpossiblesequencesandconformations,oftheorderof(20x10)^100foraproteinwith100aminoacids.AnotherkeyelementforCPDsuccessistheenergyfunctionusedtoevaluateandselectthesequencesandconformations.

OurapproachofCPDisbasedonanatomicmodeloftheproteinstructureandamolecularmechanicsenergyfunction.Animportantaspectisthesolventtreatment,representedasadielectriccontinuumwithaGeneralized-Bornterm,supplementedbyatermproportionaltothesolventaccessiblesurfacearea.Thekeyelementsofourimplementationare:1)theproteinbackboneismaintainedfixed,2)theside-chainconformationalspaceisreducedtoadiscretelibraryofrotamers,3)theenergyfunctionisdecomposedintointeractionpairs.Thefirststepconsistsincalculatingamatrixofinteractionsbetweeneachpairofrotamers.Inthenextstep,thesequence-conformationspaceisexploredwithanoptimizationalgorithm.Energyevaluationsinthissecondsteparefastthankstothepre-calculationoftheenergymatrix.TheimplementationofourCPDprocedurewillfirstbediscussed.Then,applicationstothepredictionofside-chainconformationsandtothedesignofproteinsequenceswillbepresented.

ISQBPPresident’smeeting2016–19-22June

T26:DevelopmentandaccelerationofmultiscaleQM/MMmethodsforsimulationsofcomplexbiomolecularsystems

P.Ojeda-May[1],K.Nam*[1]

[1]DepartmentofChemistry,UmeåUniversity,Sweden

Thequantummechanicalandmolecularmechanical(QM/MM)methodshavebeenanimportanttoolintheoreticalstudiesofenzymaticreactionsinsolvatedenvironments.However,becauseofcomplexityofunderlyingQMalgorithms,developmentofefficientandparallelQM/MMmethodshaslaggedbehindthedevelopmentofparallelMMsimulationalgorithms.ThisresultedinthelengthoftypicalQM/MMmoleculardynamics(MD)simulationstobeafewhundredsofpicosecondsorless,whichisrelativelytooshortforaccuratedeterminationoffreeenergiesandreactionrates.Thisalsolimitedseverelytheiruseinperforminglong-timeMDsimulations,utilizinghighperformancesupercomputersbasedonmulti-coreCPUarchitectures.ToenablelongtimescaleQM/MMmoleculardynamicssimulations,mylabhasbeendevelopingnovelmultiscaleQM/MMmethodsthatareequippedwithefficientandscalableQM/MMmethodsandintegratedwithadvancedfreeenergysimulationmethods,suchasthestringmethod.ThedevelopedmethodsincludethestableandparallelsemiempiricalQM/MMmethods,whicharebasedonMPIandhybridOpenMP/MPIparallelizationsandrobustSCFconvergenceaccelerators,andtheQM/MM-PMEmethodforefficientdeterminationoflong-rangeQM-MMelectrostaticinteractionsunderperiodicboundaryconditions.Further,thesemethodsarecombinedwithabinitio/DFTQM/MMmethodsandmultipletimestepalgorithmforenhancedaccuracyandefficiencyoftheAI-QM/MMpotentials.Withthesemethods,weareabletoachieveaboutoneorderofspeed-uprelativetothespeedofconventionalQM/MMmethods.Inthispresentation,thecurrentstatusofeachmethodispresented,andtheirapplicationtoproteinkinasesystemsisbrieflydiscussed,togetherwithfuturedirectiontoimprovetheirefficiency.

ISQBPPresident’smeeting2016–19-22June

T27:AluminumandBioligandinteractionswithphosphatecontaininggroups.

XabierLopez*[1].RafaelGrande-Aztatzi[1],JonIMujika[1],ElenaFormoso[1]

[1]KimikaFakultatea,EuskalHerrikoUnibertsitateaUPV/EHU,andDonostiaInternationalPhysicsCenter(DIPC),P.K.1072,20080Donostia,Euskadi,Spain.

Theincreasedavailabilityofaluminuminbiologicalenvironments,duetohumaninterventioninthelastcentury,raisesconcernsontheeffectsthatthissofar"excludedfrombiology"metalmighthaveonlivingorganisms.Consequently,thebioinorganicchemistryofaluminumhasemergedasaveryactivefieldofresearch.However,theexperimentaldeterminationofstructureandaffinitiesofAluminum-Bioligandcomplexesisnotwithoutdifficultiesandtheoreticalmethodshaveemergedasafundamentaltooltounveilaluminumbiochemistry.InthepresenttalkIwillreviewsomeoftherecentadvancesmadebyourgrouponthisfield.InparticularwewillfocusonAluminuminteractionswithphosphate-containingbiomoleculesusingavarietyofmethods,DFT,QM/MMandclassicalmoleculardynamicsimulations.

ISQBPPresident’smeeting2016–19-22June

T28:Structuraldynamicsandsignallingmechanismsinnuclearretinoidreceptors

Y.Chebaro,J.Eberhardt,I.Amal,R.H.Stote,A.Dejaegere*[1]

[1]EcoleSuperieuredeBiotechnologiedeStrasbourg-ESBS,France

NuclearRetinoicAcidreceptors(RARs)areligand-dependenttranscriptionalregulatorsthatformheterodimerswithRetinoidXreceptors(RXRs).Theymediatetheeffectsofretinoicacid(RA),theactivemetaboliteofVitaminA,andregulateessentialphysiologicalprocessessuchasembryonicdevelopment,organogenesis,homeostasis,vision,immunefunctionsandreproduction.TheregulationofRARsoccursthroughthebindingofretinoicacid(RA)totheligandbindingdomain(LBD),whichtriggersconformationalchangesinthereceptorthatleadtotheformationofinterfacesforthebindingofco-activatorproteins.Asidefromthisclassicalmechanismofligand-triggerednuclearreceptoractivation,recentstudiesshowedthatRARsandRXRsarecomplexallostericmodulatorsandthattheiractivitycanbefine-tunedbydifferentpost-translationalmodifications,inparticular,byphosphorylation.

StructuralinformationconcerningthemolecularmechanismunderlyingRAR’sresponsetoRAhasbeencollectedlargelybystudiesoftheLBD.AlthoughstructuralsnapshotsofessentialstructuresalongtheregulationpathwayofNRshavebeenobtainedlargelybycrystallographicstudiesoftheLBD,regulationisalsolinkedtochangesinthereceptordynamics,aswellastosubtlechangesinconformerpopulations.Thecharacterizationofthesestructuraldynamicaleffectsiscrucialtoourunderstandingoftheallostericmechanismsoccurringinthesereceptors.

Hereweusemoleculardynamicssimulationstostudythechangesinreceptorstructureanddynamicsthatoccuruponphosphorylationandhowthesechangesmayaffectthebindingaffinityfordifferentco-regulatoryproteins.Inparticular,westudiedtwophosphorylationeventsthatoccurinRARasaconsequenceoftheactionofRA.ThefirstconcernsthephosphorylationoftheRARLBDandthesecondthatofthereceptor’sN-terminaldomain(NTD).Themoleculardetailsaffordedbythesesimulationsallowustonotonlyunderstandthestructuralchangesthatoccuruponphosphorylationandhowthesechangesmayaffectthebindingaffinityfordifferentco-regulatoryproteins,butalsotounderstandallostericcommunicationrelatedtophosphorylationofnuclearreceptorsandtoidentifykeyresiduesinvolvedinthisprocess.

ISQBPPresident’smeeting2016–19-22June

T29:AnunusualallostericmechanismforregulatingproteininteractionsofSyktyrosinekinase

D.P.Hua[1],A.Roy[1],C.Feng[1],C.B.Post*[1]

[1]DepartmentofMedicinalChemistryandMolecularPharmacology,MarkeyCenterforStructuralBiology,PurdueUniversity,WestLafayette,Indiana,USA

ThephosphorylationofalinkerregionbetweentwotandemSH2domainsofSyktyrosinekinaseregulatesthebindingaffinityforSykassociationwithmembranereceptors;affinityforreceptormediatedbytheSykSH2domainsdecreases100-folduponphosphorylationoftheremotetyrosinesiteonlinkerA.Themechanismofthisallostericregulationhasbeensuggestedtobeaswitchfromahighaffinitybifunctionalbinding,mediatedthroughbothSH2domainsbindingtwophosphotyrosineresidues,toasubstantiallyloweraffinitybindingofonlyoneSH2domain.Nonetheless,thispostulatedswitchtoasingle-SH2-domainbindingmodewasrefutedbyNMRexperiments.Withtheresidue-levelpowerofNMR,wedeterminedthatphosphorylationaffectsanisomerizationstepofbifunctionalbinding.MoleculardynamicssimulationswereexploitedtoexploretheconformationaleffectsassociatedwithlinkerAphosphorylationandthusgainphysicalinsightintotheisomerizationprocess.Theresultswereindeedilluminating.ThedomainstructureofthetandemSH2domainsisstronglyperturbedbyphosphorylation.Moreover,numerouselectrostaticinteractionsbetweendomains,previouslyunknowntobeinvolvedinregulation,areperturbeduponphosphorylationandpredictedtobethebasisforregulation.

ISQBPPresident’smeeting2016–19-22June

T30:UnderstandingChargeTransferinCryptochromesandPhotolyasesviaQM/MMSimulations:ApplicationtoPhrBProtein

D.Holub[1],N.Gillet[1]*,G.Lüdemann[1],M.Elstner[1]

[1]TheoreticalChemicalBiologyKarlsruheInstituteofTechnology(KIT)InstituteofPhysicalChemistry,Germany

CryptochromeandPhotolyaserepresentaubiquitousfamilyofflavoproteinphotoreceptors.Whiletheformerisinvolvedinplantgrowth,animalcircadianrythmorperceptionoftheEarth’smagneticfield,thelatterparticipatestoDNArepairbyoxidizingCPD(cyclobutanepyrimidinedimers)or6-4photoproducts.AfterexcitationofaFAD(flavinadeninedinucleotide)cofactor,anelectrontransfer(ET)occursbetweentheproteinsurfaceandtheflavinthroughachainofseveralaromaticresidues.AwidelyconservedtryptophantriadhasbeenidentifiedbuttyrosineorafourthresiduecanbesometimesinvolvedintheET.

Recently,manyQM/MMsimulationswereperformedtounderstandthemechanismofthislongrangeelectrontransfer.Acommonissueconsistsofthelocalizationoftheelectronalongthepathwayandthedefinitionofthedifferentredoxstates.CailliezetalproposeprotocolsbasedonclassicalMDscoupledtoconstrainedDFTcalculations.Inourgroup,wefollowanotherstrategybasedontheelectronicpropagationbetweenthedifferentmolecules,efficientforthefastETsobservedintheseproteins.BothstrategiesprovideelegantconclusionsandhighlightthemechanismnatureoftheET,theroleofdifferentresidues,theexistenceofalternativepathwaysortheimportanceofthesolvent.

Wecurrentlyfocusonaprokaryotic(6-4)photolyase,thePhrBprotein.ItpresentssomeparticularitiessuchasaFe-Sclusteroratyrosineasthefirstresidueofthetriad.DirectedmutagenesisexperimentshaveshownthatmutationofthistyrosinetophenylalaninedoesnotaffectflavinreductionwhilemutationsofothersresiduesfromthetriadornotmodifytheETandtheDNArepairactivity.WestudiedthissystemusingacouplingbetweenlongclassicalandshortelectronicsimulationsatDFTBlevel.Ourresultsgiveamolecularinsightoftheeffectsofthesedifferentmutations.

ISQBPPresident’smeeting2016–19-22June

T31:NorovirusCapsidAssembly

ThibaultTubiana*[1],AnnaD.Koromyslova[2,3]GrantSHansman[2,3],YvesBoulard[1],StéphaneBressanelli[1]

[1]Interactionsandassemblymechanismsofproteinsandpeptides,B3S,I2BC,UMR9198

[2]SchallerResearchGroupattheUniversityofHeidelbergandtheDKFZ,Germany,Heidelberg69120

[3]DepartmentofInfectiousDiseases,Virology,UniversityofHeidelberg,Germany,Heidelberg69120

Norovirusesaresmallnon-envelopedviruseswithsingle-strandedpositivesenseRNA.Theyaretheleadingcauseofacuteviralgastroenteritisinhumansandanimalsandareofworldsignificanceforhealth.TheCapsidiscomposedof180copiesofasinglestructuralproteinVP1consistsoftwomaindomains:theshelldomain(S)andtheprotrudingdomain(P)whichcontainstwosubdomains(P1andP2).ThePdomainisthepartexposedtothebiologicalenvironment,itallowsinparticulartostabilizeandadjustthesizeofthecapsid.TheSdomainis,meanwhile,theassemblymoduleofviralcapsid.

OurlabandothershaveshownexperimentallythatNoroviruscapsidscanbedisassembledandreassembledinvitroaccordingtothepHofthemedium(highpH=disassembled,lowpH=reassembled).TheassemblyprocessbeginswithVP1dimerswhichquicklyproduceintermediatesof10~11dimerswhichthenslowlyassemblethemselvestocapsids.

Usingcomputationalapproachessuchashomologymodelling,simulatedannealing,moleculardynamicssimulationsinallatomandcoarsegrainsystems,wearelookingtoextendtheseskineticstudiesonhumannorovirusandthustodeterminethemolecularbasisofnoroviruscapsidassembly.

Ourfirstresultsextendpreviousstudiesalreadyachievedintheteam.ThesesresultsshowthatthedeprotonatedformoftheN-terminalarmestablishesmanysaltbridgesandallowitsstabilizationontheSdomain.OurnewSAXSexperimentsshowthatathighpHthedimerisinaquiteextendedformandverydifferentfromthecrystallographicstructure.ThankstomodelisationandmoleculardynamicstoolswehavedevelopedamodelthatfitstheexperimentalSAXSdata.OurresultsindicatethatpHandprotonationstatehaveamajorroleinthefirststepofassembly:Dimertointermediate.

ISQBPPresident’smeeting2016–19-22June

Posters

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P1:’Magicshotgun’forbacterialtoxins:aninversedockingstudyformulti-targetdrugdiscovery

P.Saenz-Méndez*[1,2],M.Eriksson[1],L.A.Eriksson[1]

[1]DepartmentofChemistryandMolecularBiology,UniversityofGothenburg,Sweden

[2]ComputationalChemistryandBiologyGroup,FacultaddeQuímica,UniversidaddelaRepública,Montevideo,Uruguay

Antimicrobialresistanceisagrowingpublichealththreat,assomepathogenshavebecomeresistanttomultipletypesofantibiotics.Therefore,thecurrentchallengeofantimicrobialdrugresearchistheidentificationofnoveldrugtargets,avoidingthedevelopmentofresistance.Pseudomonasaeruginosaisawell-knownopportunisticpathogenresponsibleformillionsofdeathperyear.ExotoxinA(ETA)isthemostpotenttoxinproducedbyP.aeruginosa,catalyzingthetransferofanADP-ribosemoietytotheeukaryoticelongationfactor2(eEF2)incellsoftheinfectedtissue.Thismodificationleadstoadysfunctioninthehostproteinsynthesiswitheventualcelldeath.TargetingP.aeruginosaETAwithsmallmoleculeinhibitorswillinterferewiththepathogen’svirulence.Asthepathogenisnotdirectlyattacked,thedefensemachinerywillnotbetriggered,andhencethemicroorganismwillunlikelydevelopdrugresistance.ETAsharescommonfeatureswithothertoxins,suchasdiphtheriatoxin(DT,fromCorynebacteriumdiphtheriae)andcholixtoxin(CT,fromVibriocholera).ThesecloselyrelatedtoxinsinspiredtheideaofdevelopingnewpotentialantibioticstargetingmainlyETA,butdisplayingadditionalactivityagainstDTandCT.Theexistenceofreceptorsforbindingmoleculesevolvesintothe‘magicbullet’concept,i.e.drugsthatgodirectlytotheirpredeterminedbiologicaltarget.However,thisone-compound-one-targetisasimplificationofreality,beingtheone-compound-multiple-targetsmodelmoreaccurate.Thisisthe‘magicshotgun’orthe‘silverbullet’concept.Tofindthat‘magicshotgun’abletotargetseveralreceptorswithoneload,inversedockingemergesastheinsilicoprototypicaltechniquetoaccomplishthatgoal.Inthiswork,wefirstselectedasetofpotentialinhibitorsofETAperformingVirtualHigh-ThroughputScreening(VHTS),andthenperformedforthefirsttimeaninversedockingstudyagainstallthreetoxinsinordertofindamulti-toxininhibitor.

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P2:Thestructureandthethermodynamicsofwateratthebindingsiteofgalectin-3withtwodiastereomersofdifferentbindingaffinities

MajdaMisiniIgnjatovic*[1],MariaLuisaVerteramo[1],FrancescoManzoni[1],OlofStenström[1],OctavCaldararu[1],MartinOlsson[1],HakonLeffler[2],UlfRyde[1],DerekLogan[1],MikaelAkke[1],andUlfJ.Nilsson[1]

[1]DepartmentofChemistry,LundUniversity,Sweden

[2]DepartmentofLaboratoryMedicine,LundUniversity,Sweden

Watermoleculescontributetoprotein–ligandbindingintwoways.First,asamedium:Waterprovideadrivingforceforthebinding,owingtothethermodynamicsofwatermoleculesdisplacedfromtheproteincavityuponligandbinding.Second,individualwatermoleculesthatstayburiedatthebindinginterfacecanformhydrogenbondswiththeproteinandtheligand,whichpromotesthestabilityoftheprotein–ligandcomplex[1].Sincethesewatermoleculesaretightlyboundandhighlyordered,theirdisplacementcanresultinhigherbindingaffinities,becauseofthegaininthetotalentropyofthesystem.

Moleculardynamicssimulationswithexplicitwatermoleculeshavebeenusedinordertostudytheroleofenthalpy,entropyandfreeenergyoftheseindividualwatermoleculesinligandbinding.WeuseGridInhomogeneousSolvationTheory[2]tostudythethermodynamicsofthesolventattheactivesiteoftheproteingalectin-3,bindingtotwodiastereomerswithdifferentexperimentalbindingaffinities.Thecalculationshelptoexplainthedifferencesinbindingaffinitiesintermsofsolvationenthalpyandsolvationentropy.Moreover,theinformationcanbeusedtofacilitateliganddesign,sincegalectin-3isaninterestingtherapeutictarget[3].

Theresultsshowmorefavorablehydrationfreeenergyofthebindingsitefortheligandwithbetterbindingaffinity.Thedifferenceof12kcal/molcomesmainlyfromthechangeinthesolvationenthalpyofthebindingsiteforthetwoligands.Weobservethatdifferentinteractionsdominatethehydrationofthetwobindingsites,andthatthecorrespondingwatermoleculeshaveadifferentmobility.

[1]Poornima,C.S.andDean,P.M.,JournalofComputer-AidedMolecularDesign9,500(1995).

[2]Nguyenetal.,JournalofChemicalPhysics137,4(2012).

[3]Yangetal.,ExpertReviewsinMolecularMedicine10,e17(2008).

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P3:Frominsilicoscreeningtoinvivoactivity:designofaselectiveinhibitorofAurorakinases

JC.Carry[1],F.Clerc[1],H.Minoux*[2],L.Schio[1],J.Mauger[6],A.Nair[6],E.Parmantier[1],R.LeMoigne[1],C.Delorme[1],JP.Nicolas[1],A.Krick[3],PY.Abécassis[3],V.Crocq-Stuerga[4],S.Pouzieux[2],L.Delarbre[2],S.Maignan[2],T.Bertrand[2],K.Bjergarde[6],N.Ma[6],S.Lachaud[1],H.Guizani[1],R.Lebel[1],G.Doerflinger[1],S.Monget[1],S.Perron[1],F.Gasse[1],O.Angouillant-Boniface[5],B.Filoche-Rommé[1],M.Murer[5],S.Gontier[5],C.Prévost[5],ML.Monteiro[5],C.Combeau[1]

[1]OncologyDrugDiscovery,Sanofi,13quaiJulesGuesde,94403Vitry-sur-Seine,France.

[2]StructureDesignInformatics,Sanofi,13quaiJulesGuesde,94403Vitry-sur-Seine,France.

[3]DispositionSafetyAnimalResearch,Sanofi,13quaiJulesGuesde,94403Vitry-sur-Seine,France.

[4]ChemicalDevelopment,Sanofi,13quaiJulesGuesde,94403Vitry-sur-Seine,France.

[5]AnalyticalSciences,Sanofi,13quaiJulesGuesde,94403Vitry-sur-Seine,France.

[6]CombinatorialTechnoCenter,Sanofi,2090EastInnovationParkDr.,OroValley,AZ85755-1965,USA

TheAuroraproteinfamily(AuroraA,BandC)belongstotheserine/threoninekinases.Theyplayakeyroleincelldivision.Theyarealsoaberrantlyexpressedinavarietyofsolidandliquidtumors,whichmakesthemattractivetargetsfornewcancertherapies.

WereportherethediscoveryofanovelclassofAurorakinasesinhibitors.Startingfromavirtualscreeningcombiningapharmacophoricapproachandhighthroughputdockinginto4differentconformationsofAuroraA,3500compoundswereselectedandtestedinanAuroraAbiochemicalassayforenzymaticactivityinhibition.Fivechemicalserieswereidentifiedand1,2,4,6,7,8-hexahydro-5H-Pyrazolo[3,4b][1,7]naphthyridin-5-onesrapidlyemergedonthebasisofselectivitydata.

UsingX-raystructureofcompound1incomplexwithAurora2,chemicalmodificationsledasignificantimprovementofAuroraAinhibitionfromanIC50of9800nMforcompound1toandIC50of4nMforcompound2.Compound2wasfoundexclusivelyselectiveforAurorainapanelof64kinasesbutalsoexhibitedasignificantinhibitionofphosphodiesterase3(PDE3)withanIC50of270nM.

ToimproveselectivityofthechemicalseriesversusPDE3,structure-baseddrugdesignwasappliedusingbothX-raystructuresandadockingmodel.

Wehaveeventuallyidentifiedcompound3whichcombinedhighpotencyonallthreeisoformsofAurora(i.e.IC50=0.6nM(AuroraA);1nM(AuroraB/Incenp);3nM(AuroraC/Incenp))withanoutstandingselectivityprofileagainstapanelofover110kinasestested.Rationalofthisexquisiteselectivitywillbediscussed,basedonstructuralinformationavailableforthiscompound.

ISQBPPresident’smeeting2016–19-22June

Finally,invivoefficacyonrelevanttumormodelshasbeendemonstratedforcompound3.

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P4:TowardsDynamicPharmacophoreModelsbyCG-MDSimulations

NicholasMichelarakis*[1],ZaraSands[2],MarkS.P.Sansom[1],&PhillipJ.Stansfeld[1]

[1]DepartmantofBiochemistry,UniversityofOxford,SouthParksRoad,Oxford,OX13QU,UnitedKingdom

[2]UCBPharmaS.A.,CheminduForiest,B-1420Braine-l'Alleud,Belgium

Pharmacophoremodelsplayakeyroleincomputer-aideddrugdiscovery,playinganimportantroleine.g.virtualscreeningofchemicaldatabases,denovodrugdesign,andleadoptimization.Structure-basedmethodsfordevelopingpharmacophoremodelsareofespecialimportance,andtherehavebeenanumberofstudiescombiningsuchmethodswiththeuseofmoleculardynamics(MD)simulationstomodelproteinflexibility.Atthesametimetherehavebeenongoingdevelopmentsinmulti-scalesimulations,combiningatomisticandcoarsegrainedMDsimulationsinasequentialfashion,toexploretheinteractionsofproteinswithmembranesandtheirlipids[1,2]andwithoneanother[2].HerewedescribetheuseofCG-MDsimulationstoexploretheinteractionsofCG-particleprobeswithproteins,combinedwithatomisticMDsimulationstomodeltheconformationaldynamicsoftargetproteins.Usingcyclindependentkinase2(CDK2)asatestcase,wedemonstratethepotentialutilityofthisapproachforidentificationofligandbindingsites,andaspartofanoverallprocessofstructure-baseddevelopmentofpharmacophoremodels.

[1]Stansfeld,P.J.&Sansom,M.S.P.(2011)Fromcoarse-grainedtoatomistic:aserialmulti-scaleapproachtomembraneproteinsimulations.J.Chem.Theor.Comp.7:1157-1166

[2]Hall,B.A.&Sansom,M.S.P.(2009)Coarse-grainedMDsimulationsandprotein-proteininteractions:thecohesin-dockerinsystem.J.Chem.Theor.Comput.5:2465–2471

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P5:MolecularlevelcharacterizationofconformationalchangesinducedbydiarylideneketoneinhibitorsintoTrypanosomacruzitriosephosphateisomerasethroughmoleculardynamicssimulations

L.Minini[1,2],E.Aguilera[2],M.González[2],H.Cerecetto[3],G.Álvarez[4],A.Merlino*[1]

[1]DepartmentofTheoreticalandComputationalChemistry,FacultaddeCiencias,UniversidaddelaRepública,Uruguay

[2]DepartmentofMedicinalChemistry,FacultaddeCiencias,UniversidaddelaRepública,Uruguay

[3]DepartmentofRadiopharmacy,CentrodeInvestigacionesNucleares,UniversidaddelaRepública,Uruguay

[4]DepartmentofBioactiveMolecules,CentroUniversitarioRegionalLitoralNorte,UniversidaddelaRepública,Uruguay

Chagasdisease,causedbytheprotozoanparasiteTrypanosomacruzi,havebeenlargelyconsideredaneglectedinfection.Currently,6-7millionpeopleareestimatedtobeinfectedworldwide,mostlyinLatinAmericawherethediseaseisendemic.Inspiteoftheeffortsmadeinthelastyearstofindsafeandeffectivecompoundstotreatthisdiseasefewmoleculeshavearisenaspromisingdrugcandidates.Therefore,furtherprogressintheresearchanddevelopmentofnovelcompoundswiththepotentialtobecomeusabledrugsiscrucial.Inthiscontext,ourresearchgrouphasrecentlyreportedsomediarylideneketoneswhichprovedtobeactiveagainstT.cruziepimastigotes.Inparticular,threeofthesecompoundsresultverygoodandselectiveinhibitorsofT.cruzitriosephosphateisomerase(TcTIM),avalidatedtargetagainstthisparasite.However,themechanismofenzymeinhibitionhasnotyetbeenfullyelucidated.Inthiswork,weperformed100nsmoleculardynamicssimulationsofTcTIM-diarylideneketonecomplexesinordertocharacterizeatadetailedmolecularlevelthefundamentalinteractionsandeffectsofthesecompoundsinproteindynamicsandfunction.OurresultsshowedthatwhilemildinhibitorsresidelittletimeintotheirbindingsitethemostpotentinhibitorofTcTIM[(2E,6E)-2,6-Bis((E)-3-(furan-2-yl)allylidene)cyclohexanone]bindsclosetotheactivesiteoftheenzymeblockingsubstratebindingandinducingimportantconformationalchangesthataffecttheproperpositioningofprotein´sloopsthatareinvolvedincatalysis.Ourtheoreticalresultswereabletoexplaintheexperimentaldataandhaveprovideduswithusefulinformationforfutureprospectsonrationaldrugdesign.

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P6:Insilicodesign,DNAinteraction,synthesisandbiologicalevaluationofinhibitorsofhypoxia-induciblefactor(HIF-1)asantitumoragents.

L.Minini[1],AMerlino[1],M.DeNegri[2],M.L.Lavaggi*[2]

[1]LaboratoriodeQuímicaTeóricayComputacional,FacultaddeCiencias,UniversidaddelaRepública.

[2]LaboratoriodeQuímicaBiológicaAmbiental,CentroUniversitariodeRivera,UniversidaddelaRepública.

Solidtumorscontainhypoxicregions,whichconfersresistancetoradiationandchemotherapy,butinturnoffersanattractivedifferencebetweennormalandtumorcellsthatcanbeexploitedtoobtainselectivedrugsdirectedtospecifictargetsonhypoxiccells.Hypoxiainduceschangesingeneexpressionprofilethroughtheinductionofatranscriptionalfactorcalledhypoxia-induciblefactor,HIF-1.Thisproteinactivatesthetranscriptionofgenesrelatedtocellsurvival.Aninterestingstrategyforthedevelopmentofantitumoragentsistheuseofprodrugs,whichafterselectivebioreductionunderhypoxicconditions,interactwithDNAaffectingthebindingsiteofHIF-1.

Inthisworkwehavedesignedderivativesofamino-phenazine5,10-dioxidesincludinglateralgroupswiththepotentialabilitytoactasDNAinteractiveagentsthatcouldbindselectivelytothe5'-ATACGTG-3´andtherebypreventinteractionwithHIF-1.Todeterminethepossibleinteractionmode,moleculardockingcalculationsandmoleculardynamicssimulationswerecarriedout.SomeofthederivativesproposedinteractwiththeregionofinterestandalsointercalateintoDNAwithgoodaffinity.Synthesisofthosecompoundsthatshowedanadequatedegreeofaffinitywiththeintendedtargethasbeenperformed.ResultsshowdifferentmodesofDNAbindingofthecompounds,furtherbiologicalstudieswillbeperformedtoachievemoreresultsconfirmingthedifferentmodesofaction.

ISQBPPresident’smeeting2016–19-22June

Topic:Drugdesign

P7:SHSF:AnewandimprovedscoringfunctionforAutoDockVinaaddressingsigmaholeinteractions

M.Koebel*[1],G.Schmadeke[1],S.Sirimulla[1]

[1]DepartmentofBasicScience,St.LouisCollegeofPharmacy,UnitedStates

Unconventionalnon-covalentinteractionsaregainingincreasedattentionindrugdesignresearchasoflately.Halogenbonds,whichutilizeasigmaholeforformation,arenowconsideredimportantnon-covalentinteractionsforuseinrationaldrugdesign.Sulfur,whichhasahighpresenceinligands,isalsoknowntoexhibitasigmahole.Mostofthecurrentdockingprogramshoweverdonotaccountforthesesigmaholeinteractions.Mostrecentlywehavedevelopedascoringfunction(XBSF)toaccountforhalogenbondinteractionsinprotein-ligandcomplexes.Inthiscurrentstudy,wepresentanewscoringfunctionthatalsoaccountsforavarietyofsigmaholeinteractionsincludingsulfur,andwetermeditas“SigmaHoleScoringFunction”orSHSF.ThebasisforthenewscoringfunctionanditsimplementationinAutoDockVinaarepresented.

ISQBPPresident’smeeting2016–19-22June

Topic:Enzymecatalysis

P8:MoleculardynamicssimulationsofBiofluidLipases:understandingbiofluidenzymesstabilityforhyperthermophilicbiosynthesis

BiancaPérez*[1],RichardSessions[2],AndreaColetta[3],JulieGrouleff[3],FrankJensen[3],ZhengGuo[1],AdamPerriman[4],BirgitSchiøtt[3,5].

[1]DepartmentofEngineering,AarhusUniversity,Aarhus8000,Denmark;

[2]SchoolofBiochemistry,UniversityofBristol,BristolBS81TD,U.K;

[3]DepartmentofChemistry,AarhusUniversity,Aarhus8000,Denmark;

[4]SchoolofCellularandMolecularMedicine,UniversityofBristol,BristolBS81TD,U.K;

[5]InterdisciplinaryNanoscienceCenter,AarhusUniversity,Aarhus8000,Denmark.

Enzymecatalysishasopenednewdoorsforgreenprocessesbutitsextensiveapplicationhasbeenlimitedbythelowthermostabilityofenzymes.Arecentreportshowedthatsolvent-freebiofluidsoflipase-polymersurfactantnanoconjugatesretaincatalyticactivityatupto150°Cwithhalfdenaturationtemperaturesofaround170oC.Here,themesophileRhizomucormiehei(RML)andthethermophileThermomyceslanuginosus(TLL)coatedwithananionicpolymersurfactant,respectively,displayedactivityunderanhydrousconditionschallengingthetraditionalbeliefthatenzymesrequireawaterhydrationspheretobeactive.Nevertheless,furtherworkisneededtounderstandwhetherthesurfactantsmayimpedetheinteractionofthesubstratewiththecatalytictriadandifotherenzyme’smodificationscanbemadetooptimizecatalyticactivitytowardshydrolysisandesterificationathightemperatures.Basedontheabove,wepresentdatafrommoleculardynamicsimulationsstudiesofthesystemsinquestiontoevaluatethestabilityofthelipasebioconjugatesathightemperature.Theresultsprovideagatewaytoabetterunderstandingofthethermostabilityofthebiofluidenzymes,andmoreover,theyprovidenewinsideforthedesignofthenextgenerationoflipase-polymernanoconjugates.

ISQBPPresident’smeeting2016–19-22June

Topic:Enzymecatalysis

P9:UnderstandingCatalysisintheHepatitisDeltaVirusRibozymeusingQM/MMStringSimulations

A.Ganguly*[1],P.Thaplyal[2],P.Bevilacqua[2],S.Hammes-Schiffer[3]

[1]Max-Planck-InstitutfuerKohlenforschung,Muelheim,Germany

[2]DepartmentofChemistry,PennsylvaniaStateUniversity,USA

[3]DepartmentofChemistry,UniversityofIllinoisatUrbana-Champaign,USA

Thehepatitisdeltavirus(HDV)ribozymeperformssite-specificcleavageinRNA.Thisribozymeusesacombinationofmetalionandnucleobasecatalysistoeffecttheself-cleavagereaction.Weperformedquantummechanical/molecularmechanical(QM/MM)stringsimulationstoinvestigatethemechanismofthecatalyticreaction.Ourresultsprovidekeyinsightsintothemachineryofribozymecatalysis.Inparticular,ourstudieselucidatetheroleofanactivesitemetalioningoverningthereactionpathway.

ISQBPPresident’smeeting2016–19-22June

Topic:Methodologicaladvances

P10:MolecularIntegrationSimulationToolkit-interfacingnovelintegratorswithMolecularDynamicscodes.

I.Bethune*[1],E.Breitmoser[1],B.J.Leimkuhler[2]

[1]EPCC,TheUniversityofEdinburgh,UK

[2]MaxwellInstituteforMathematicalSciencesandSchoolofMathematics,TheUniversityofEdinburgh,UK

ModernproductionMolecularDynamicscodesrepresentasignificantinvestmentofeffortbythecommunitytodevelophighlyoptimisedforceevaluationroutinesabletotakeadvantageofstate-of-thearthardwaresuchasGPUsandmulti-coreCPUs.However,thiscomesatacostofcodecomplexitywhichmakesithardfornewintegrationalgorithmstobeimplementedinthesepackages.Thiscreatesacatch-22foralgorithmdevelopement-ifnewalgorithmscannotbeimplementedandtestedinproductioncodesitmaybeimpossibletodemonstratetheirbenefitsoverexistingschemes;conversely,ifthecommunitycannotseethebenefitofnewalgorithms,codedeveloperswillnotspenttimeimplementingthem!

TheMolecularIntegrationSimulationToolkit(MIST)libraryisasolutiontothisproblembyprovidingplug-instoexistingoptimisedMDcodes,coupledwithasimpleinterfaceforthedevelopmentofnewintegrationmethods.MISTcurrentlyprovidesinterfacestoGROMACS,AmberandNAMD-Lite,allowingittobenefitfromOpenMPandGPUaccelerationforforce-evaluation.Severalstandard(Verlet,Leapfrog)andnew(LangevinDynamicsbasedonaBAOABsplitting)integratorshavebeenimplementedtodate.TheMISTlibraryinterfaceresultsinsignificantease-of-development,atnegligiblelossofperformance.Newintegrationalgorithmsareimplementedonce,inacode-agnosticmanner,andcanthenbeimmediatelydeployedinalltheMDcodessupportedbyMIST.

Aswellasalgorithmsforsamplingthecanonicalandmicro-canonicalensembles,MISTisalsoaplatformforbuildingmoreadvancedschemes.Forexample,wehaveimplementedanextended-systemmethodfor'ContinuousTempering',whichenablescomputationoffreeenergymapsinsystemswithlargeenergybarriers.

SeveralnewfeaturesareunderdevelopmentinMIST-newconstraintsolversforextremelylongtimestepsandmulti-timestepsplittings,MPIparallelisation,andsupportformoreMDcodes.Wewelcomethecommunity'sinputondirectionforfuturedevelopment.

ISQBPPresident’smeeting2016–19-22June

Topic:Methodologicaladvances

P11:Buildingadatabaseof3DbiologicalshapesfortheinterpretationofXFELdiffractionpatterns

S.P.Tiwari[1],F.Tama[1,2],O.Miyashita[1]

[1]RikenAdvancedInstituteforComputationalScience,Kobe,Japan

[2]DepartmentofPhysics,GraduateSchoolofScience,NagoyaUniversity,Nagoya,Japan

X-rayfreeelectronlaser(XFEL)scatteringexperimentshasbeendescribedasthefutureofstructuralbiology.Thetechniquehasseveraladvantages,includingitsabilitytoprobeasingleparticlesamplewithouttheneedforcrystallisation,andtoproducediffractiondatabeforethesampleisdestroyedbyradiation.However,resolvingstructuresfromXFELdiffractionpatternscanbechallengingduetothephaseproblem.Consideringthenoveltyofthetechnique,thereisalsolimiteddataavailabletoprovideinitialmodelsthatfitnewdiffractionpatterns.Therefore,weconsiderastrategytoprovideefficientinterpretationofXFELdatabysearchingthemagainstadatabaseofhypotheticalbiologicalshapestoobtainaninitialstructuralmodel.Tobuildadatabaseofbiologicalshapes,weassemblevariousthree-dimensional(3D)structuresinexistingstructuredatabanks,suchastheElectronMicroscopyDataBank(EMDB).Wecanthenreducetheassembleddatasettoaminimalyetdistinctsetofhypotheticalbiologicalshapes.Inthefirstpartofthisassembly,wepresenttheanalysisofsingleparticlecryo-electronmicroscopy(cryo-EM)structures.Here,weanalysethevariationintheshapesthatexistswithinthe3Dcryo-EMmaps,andwithintheirsimulatedtwo-dimensional(2D)projectionimages.Thisanalysisprovidesuswiththeextenttowhich2Dimagesoftwodistinct3Dshapescanbesimilar,givingusanideaoftheexpecteddegeneracywhenwecompareexperimentaldatatoahypotheticalbiologicalshape.Ingeneral,weexpectthatwithasufficientnumberof3DshapeswillallowustoprovidecandidatemodelsfornewXFELdataeffectively.

ISQBPPresident’smeeting2016–19-22June

Topic:Methodologicaladvances

P12:ANovelThree-layerMultiscaleQM/MM/CGApproach

P.Sokkar*[1],E.Boulanger[2],W.Thiel[1],E.SanchezGarcia[1]

[1]DepartmentofTheoreticalChemistry,Max-Planck-InstitutfürKohlenforschung,MülheimanderRuhr,Germany.

[2]DepartmentofBiochemistryandMolecularBiophysics,UniversityofChicago,Chicago,UnitedStates

Wepresentanovelquantummechanics/molecularmechanics/coarse-grained(QM/MM/CG)multiresolutionapproachforsolvatedbiomolecularsystems.Inthisapproach,thechemicallyimportantregionistreatedattheQMlevel.ThebiomolecularenvironmentisdescribedbyanatomisticMMforcefield,andthesolventismodeledwiththeCGMartiniforcefieldusingstandardorpolarizable(pol-CG)waterdefinitions.InteractionswithintheQM,MM,andCGregions,andbetweentheQMandMMregions,aretreatedintheusualmanner,whereastheCG–MMandCG–QM(vdW)interactionsareevaluatedusingthevirtualsitesapproach.ThechargedMMandCGparticlesaretreatedasexternalpointchargesintheQMhamiltonian.Theaccuracyandefficiencyofourimplementationistestedfortwoenzymes,chorismatemutase(CM)andp-hydroxybenzoatehydroxylase(PHBH).InCM,theQM/MM/CGpotentialenergyscansalongthereactioncoordinateyieldreactionenergiesthataretoolarge,bothforthestandardandpolarizableMartiniCGwatermodels,whichcanbeattributedtoadverseeffectsofusinglargeCGwaterbeads.TheinclusionofanatomisticMMwaterlayer(10ÅforunchargedCGwaterand5ÅforpolarizableCGwater)aroundtheQMregionimprovestheenergyprofilescomparedtothereferenceQM/MMcalculations.InanalogousQM/MM/CGcalculationsonPHBH,theuseofthepol-CGdescriptionfortheouterwaterdoesnotaffectthestabilizationofthehighlychargedFADHOOH-pOHBtransitionstatecomparedtothefullyatomisticQM/MMcalculations.Detailedperformanceanalysisinaglycine–watermodelsystemindicatesthatcomputationtimesforQMenergyandgradientevaluationsatthedensityfunctionallevelaretypicallyreducedby40–70%forQM/MM/CGrelativetofullyatomisticQM/MMcalculations.

ISQBPPresident’smeeting2016–19-22June

Topic:Methodologicaladvances

P13:TheBio3Dproject:InteractiveToolsforStructuralBioinformatics

LarsSkjærven*[1],ShashankJariwala[2],Xin-QiuYao[2],GuidoScarabelli[2],andBarryJ.Grant[2]

[1]DepartmentofBiomedicine,UniversityofBergen,Norway

[2]DepartmentofComputationalMedicineandBioinformatics,UniversityofMichiganMedicalSchool

WepresentextensiveupdatestoBio3D,apackageforbothinteractiveandbatchanalysisofbiomolecularstructure,sequenceandmolecularsimulationdata.Theseupdatesincludeuniquehigh-throughputensemblenormalmodeanalysisforexaminingandcontrastingthedynamicsofrelatedproteinswithnon-identicalsequencesandstructures,newconsensusmethodsforquantifyingdynamicalcouplingsandtheirresidue-wisedissectionfromcorrelationnetworkanalysis,interactivestructureensemblevisualizationaswellasmulticoresupportformanytimeintensivetasks.WedemonstrateanewonlineWebAppserverpoweredbyBio3Dforcomparativeproteinstructureanalysis.Thisserverfacilitates:(1)Theidentificationofrelatedproteinstructurestouserspecifiedthresholdsofsimilarity;(2)Theiralignmentandstructuresuperposition;(3)Sequenceandstructureconservationanalysis;(4)Inter-conformerrelationshipmappingwithprincipalcomponentanalysis,and(5)ensemblenormalmodeanalysisforcomparisonofpredicteddeformationsacrossproteinfamilies.TheWebApp,offerunparalleledcapabilitiesforensembleanalysisofproteinstructuresinauserfriendlywebbrowserenvironmentfromhttp://thegrantlab.org/bio3d/webapps.ThepreviousversionofBio3Dhasbeendownloadedbyover13,700researchersandcitedover200timesinthelastsixyears.MergingthesenewmethodswiththeexistingBio3Dinfrastructurerepresentsanimportantadvancethatwehopewillfurtherstimulatebiophysiciststousestructuralbioinformaticsmethodsasanaidinsolvingtheirresearchproblems.TheBio3DpackageandassociatedWebAppsaredistributedwithfullsourcecodeandextensivedocumentationunderaGPL2licensefromhttp://thegrantlab.org/bio3d/.

ISQBPPresident’smeeting2016–19-22June

Topic:Methodologicaladvances

P14:MappingtheFunctionalGroupRequirementsoftheOccludedBindingPocketoftheβ2-AdrenergicG-ProteinCoupledReceptorusingGrandCanonicalMonte-Carlo/MolecularDynamicsCoupledSiteIdentificationbyLigandCompetitiveSaturationSimulations

A.D.MacKerellJr.*[1],S.K.Lakkaraju[1],E.P.Raman[1],W.Yu[1]

[1]DepartmentofPharmaceuticalSciences,SchoolofPharmacy,UniversityofMaryland,Baltimore,USA

β2-adrenergicG-proteincoupledreceptor(B2AR)isanimportanttherapeutictargetforAsthmaandotherobstructivepulmonarydiseases.Theligandbindingpocket(LBP)inthisandanumberofotherdrugtargetsisdeeplyburied,offeringsignificantchallengestocomputer-aideddrugdesignapproaches.SiteIdentificationbyLigandCompetitiveSaturation(SILCS)isanin-situfragmentsamplingmethodthatmapsthespatialdistributionsandapproximateaffinitiesofchemicallydiversefunctionalgroupsonamacromoleculethroughmoleculardynamics(MD)simulationsofthemacromoleculeinanaqueoussolutionofsmallmolecules.Notableisthesimultaneousinclusionofwatersandproteinflexibilitysuchthatthemethodaccountsforligandandbindingsitedesolvationwhenmappingtheaffinitypatternsofthedifferentfragments(FragMaps).ToprobeanoccludedLBP,anovelGrand-CanonicalMonte-Carlo/MD(GCMC/MD)strategyisextendedtotheSILCSmethodology.GCMCdrivesthefragmentsandexplicitsolventsamplingoftheoccludedpocket,andtheMDallowsfortheconformationalsamplingofthemacromoleculeinthepresenceofthesmallmolecules,whichisusefulinidentifyingregionsintheLBPthatwerenotidentifiedasaccessibleinthecrystalconformation.GoodagreementisobtainedbetweentheFragMapsandthepositionsofchemicallysimilarfunctionalgroupsofligandsobservedinthecrystalstructuresofB2AR.Ligandgridfreeenergy(LGFE),anapproximateestimationofbindingaffinityderivedfromFragMapshadgoodcorrelationwiththeexperimentallymeasuredbindingaffinityfordiverseligands.CleardifferenceswerefoundintheFragMapsattheLBPacrosstheactivatedandinactivatedconformationsoftheB2AR.Thesedifferenceswereusefulindeterminingthenatureofaligandthatwouldpreferentiallybindtooneofthetwostatesandconsequentlyguidedrugdesign.

ISQBPPresident’smeeting2016–19-22June

Topic:Methodologicaladvances

P15:ConformationalclusteringofMDtrajectoriesusingstochasticproximityembedding

JérômeEberhardt*[1],RolandH.Stote[1],AnnickDejaegere[1]

[1]InstitutdeGénétiqueetdeBiologieMoléculaireetCellulaire(IGBMC)-CNRS:UMR7104Inserm:U964,UniversitédeStrasbourg-Parcd’Innovation1rueLaurentFries-BP1014267404ILLKIRCHCEDEX,France

Moleculardynamics(MD)simulationsarewidelyusedtoexploreconformationalensemblesofbiologicalmacromolecules.Withtheincreasingamountofcomputationalpoweravailableandthedevelopmentofenhancedsamplingmethods,,longtimescaleandcorrespondinglyimportantconformationalrearrangements,suchasfolding/unfoldingevents,arebecomingmoreandmoreaccessible.Asaconsequence,theanalysisofthelargesetsofconformationsgeneratedbyMDbecomeschallengingduetothecomplexityoftheunderlyingenergylandscape.Differentclusteringmethods,suchashierarchicalclusteringordimensionalityreduction(PCA,ISOMAP...)havebeenappliedtoMDsimulations,butthereremainsaneedforimprovedclusteringstrategiesthatcanhandlenonlineardataand/orbeappliedtoverylargedatasets.Weimplementedandtestedthepivot-basedversionoftheStochasticProximityEmbeddingmethod[1]inthecontextoflargeMDdatasets.Theadvantagesofthealgorithmintermsofdatastorageandcomputationalefficiencywillbepresented,aswellastheimplementationrealized.Applicationsandtestingtotheanalysisof15µsclassicalMD[2]and1µsaMDofa56-residue⍺/βsubdomainofproteinGandthe235-residueligandbindingdomainofnuclearreceptorRXR⍺,respectively,willbediscussed.Thedatapresentedshowsthepromiseofthismethodtoorganizeandvisualizelargeensemblesofconformations.

[1]Agrafiotis,D.K.(2003).Stochasticproximityembedding.Journalofcomputationalchemistry,24(10),1215-1221.

[2]Guarnera,E.,Pellarin,R.,&Caflisch,A.(2009).Howdoesasimplified-sequenceproteinfold?.Biophysicaljournal,97(6),1737-1746.

ISQBPPresident’smeeting2016–19-22June

Topic:Nucleicacids

P16:TwistingDNA

AnnaReymer*[1],KrystynaZakrzewska[2],RichardLavery[2]

[1]Departmentofchemistryandmolecularbiology,UniversityofGothenburg,Gothenburg,Sweden

[2]MolecularmicrobiologyandStructuralBiochemistry,UniversitéLyon1/CNRSUMR5086,IBCP,Lyon,France

AbilityofDNAtodynamicallychangeitssuperhelicalstateiscentraltomanybiologicalfunctions,includingregulationofgeneexpression,repair,andpackaginginthecell.ToaddressconformationalmechanicsofDNAduringsupercoilingtransitionswedesignedanewstructuralconstraint,acomplementtostandardall-atommoleculardynamicssoftware,implementedinAmber12softwarepackage.Theconstraintcontrolsthevalueoftotaltwistbetweenanytwobase-pairsinaDNAmolecule,whileitdoesnotrestrictanyotherDNAhelicalparameter.TheconstraintcanbeappliedtoDNAmoleculesofanylengthandcurvature,aloneorincomplexwithothermolecules.ThisallowsforthefirsttimetostudyDNAinconditionsresemblingitsinvivostate,whereDNA’stopologyissubstantiallyrestricted.Asaproofofconcept,weappliedtherestrainttotwodifferentlinearDNAmolecules,changingtheirsuperhelicaldensityfrom-0.15to+0.15,whichcorrespondstounder-oroverwindingby5degreesperbasepairstep.DNAresponsetothetorsionalstressappearedtobediscontinuous-certaindinucleotidestepsappeartobemoresusceptibletoreducingorincreasingtheirtwist.Inparticular,CpGstepswerefoundtoactas“twist”-capacitors,suggestingthatsomeDNAsequencesallowmoreefficientredistributionofsuperhelicaldensity

ISQBPPresident’smeeting2016–19-22June

Topic:Nucleicacids

P17:TautomericequilibriumofuracilinribosomalA-site

Y.Hartono*[1].L.Nilsson[1]

[1]DepartmentofBiosciencesandNutrition,KarolinskaInstitutet,Sweden

IthasbeenobservedinseveralstructuresofribosomethatU*-Ganticodon-codonbasepairintheA-siteisinWatson-Crickgeometryinsteadoftheexpectedwobble.InonecasetheinteractionisbetweentRNAValcmo5UACandcodonGUG.Alsoofnote,thisparticulartRNAisabletoincorporatevalinewithallValcodonboxGU(U/C/A/G).Sinceuridineismodified,theauthorsspeculatethatinthecmo5U-Gbasepair,cmo5Umightbeinenolformandthemodifiedmoeitymightcontributetotheequilibriumshift.Inanothercase,itisbetweentRNALysU*UUandcodonGAA.Here,thebasesarenotmodified,andtheauthorsspeculatethateitherUorGmightbeintheenolform.OurpreliminaryQMcalculationinvacuumandsolventofcmo5U-Gbasepairshowsthatalthoughtheextraneousmoeitydoescontributetoashiftinthetautomericequilibrium(enolinstabilityrelativetoketodecreasesfrom10.79kcal/molinuracilto4.52kcal/molincmo5UbasepairedtoG),theketotautomerisstillfavourable.Inthisstudy,weaimtoincludetheeffectoftheenvironment,mainlyribosomalA-siteenvironment,intoaccount.Todothis,weperformmoleculardynamicssimulation(MD),performQM/MMpointcalculationsontheMDsnapshots,andanalysetheresultwithQM-Non-BoltzmannBAR(QM-NBB),whichcombinesBennet'sacceptanceratio(BAR),acommontoolforfreeenergycalculation,withQM/MMcalculation.

ISQBPPresident’smeeting2016–19-22June

Topic:Nucleicacids

P18:Conformationalselectionanddynamicadaptationuponlinkerhistonebindingtothenucleosome

MehmetAliÖztürk[1,2],GeorgiV.Pachov[1],RebeccaC.Wade[1,3,4]*andVladCojocaru[5,6]*

[1]MolecularandCellularModelingGroup,HeidelbergInstituteforTheoreticalStudies(HITS),Heidelberg,69118,Germany

[2]TheHartmutHoffmann-BerlingInternationalGraduateSchoolofMolecularandCellularBiology(HBIGS),HeidelbergUniversity,Heidelberg,69120,Germany

[3]CenterforMolecularBiology(ZMBH),DKFZ-ZMBHAlliance,HeidelbergUniversity,Heidelberg,69120,Germany

[4]InterdisciplinaryCenterforScientificComputing(IWR),Heidelberg,69120,Germany

[5]ComputationalStructuralBiologyLaboratory,DepartmentofCellularandDevelopmentalBiology,MaxPlanckInstituteforMolecularBiomedicine,Münster,48149,Germany

[6]CenterforMultiscaleTheoryandComputation,WestfälischeWilhelmsUniversity,Münster,Germany

LinkerhistonesareessentialforDNAcompactioninchromatin.Theybindtonucleosomesina1:1ratioformingchromatosomes.AlternativeconfigurationshavebeenproposedinwhichtheglobulardomainofthelinkerhistoneH5(gH5)ispositionedeitheron-oroff-dyadbetweenthenucleosomalandlinkerDNAs.However,thedynamicpathwaysofchromatosomeassemblyremainelusive.Here,westudiedtheconformationalplasticityofgH5inunboundandoff-dyadnucleosome-boundformswithclassicalandacceleratedmoleculardynamicssimulations.WefindthattheunboundgH5convertsbetweenopenandclosedconformations,preferringtheclosedform.However,theopengH5contributestoamorerigidchromatosomeandrestrictsthemotionofthenearbylinkerDNAthroughhydrophobicinteractionswiththymidines.Moreover,theclosedgH5opensandreorientsinacceleratedsimulationsofthechromatosome.Browniandynamicssimulationsofchromatosomeassembly,accountingforarangeofamplitudesofnucleosomeopeninganddifferentnucleosomeDNAsequences,supporttheexistenceofbothon-andoff-dyadbindingmodesofgH5andrevealalternative,sequenceandconformation-dependent,chromatosomeconfigurations.Takentogether,thesefindingssuggestthattheconformationaldynamicsoflinkerhistonesandnucleosomesfacilitatealternativechromatosomeconfigurationsthroughaninterplaybetweeninducedfitandconformationalselection.

Reference:Öztürketal.2016,NucleicAcidsResearch,inpress

ISQBPPresident’smeeting2016–19-22June

Topic:Other

P19:Effectofacosolventinbindingeventsofhydrophobicmolecules

C.Senac[1],P.Fuchs[2],W.Urbach[1,3]andN.Taulier[1]

[1]SorbonnesUniversité,UPMCUnivParis6,CNRS,INSERM,Laboratoired'ImagerieBiomédicale,Paris,France

[2]InstitutJacquesMonod,CNRSUMR7592,UniversitéParisDiderot,Paris,France

[3]LaboratoiredePhysiqueStatistiquedel'EcoleNormaleSupérieure,UMRCNRS8550Paris,France

Thesearchofnewdrugsishinderedbythefactthatanincreasingnumberofdrugcandidatesarehydrophobic.Intheexperimentalinvitroinvestigationofdrugbindingproperties,mostpharmaceuticalcompaniesuseadditivestoincreasewatersolubilityofthesemostlyhydrophobicligands.Oneofthemostusedadditiveisdimethylsulfoxide(DMSO)despitethefactthatlittleisknownaboutitseffects.Inparticular,itisstillnotwellunderstoodhowDMSOmodifiesthehydrationofthehydrophobicbindingsitesofboththepharmaceuticaltargetanditsligand.

InordertobetterunderstandtheinteractionofDMSOwithhydrophobicsurfacesanditsimpactonthebindingofhydrophobicligands,wehaveperformedexperimentalandmoleculardynamicsstudiesoftheinteractionbetweenγ-cyclodextrin(γ-CD),asmallmoleculehavingasinglehydrophobicbindingsite,withitsligand1-adamantanecarboxylicacid(ADA).Ourvolumetricmeasurementsshowedthatthebindingconstantissignificantlygreaterinasolutionof5%DMSOthaninpurewater.OurmoleculardynamicssimulationsprovidedmolecularinsightsontheeffectofDMSOinthebindingeventinthepresenceandabsenceof5%DMSO.WeobservedacompetitionbetweenDMSOandthehydrophobicpartofADAforγ-CD’sinteractionsiteduringthebindingevent.Surprisingly,DMSOincreasedthemobilityofADAwhenitwasboundtoγ-CD,whileatthesametimeADAmademoreH-bondswithγ-CDthanwithwater.DMSOseemedtostabilisetheinteractionbetweenADAandγ-CD.FreeenergycalculationsonthesesystemsareongoinginordertoelucidatetheDMSOcontributioninthethermodynamicsofthesystem.

ThisworkshouldhelpprovideabetterrationalizationinthedesignofpotenthydrophobicligandsknowingtheDMSOcontributiontotheirbindingproperties.

ISQBPPresident’smeeting2016–19-22June

Topic:Other

P20:SolventdynamicscontrolsthestabilityandreactivityofGrignardreagents.

RaphaelM.Peltzer*[1],[2],OdileEisenstein[2],[3],MicheleCascella[1],[2]

[1]DepartmentofChemistry,UniversityofOslo,Norway

[2]CentreforTheoreticalandComputationalChemistry(CTCC),Norway

[3]CNRS,Universite’deMontpellier,France

TheGrignardreactioniswidelyappliedinorganicchemistryforsynthesisofacarbon-carbonbondbetweenanucleophilicorganometallichalideofnominalformulaR-Mg-X,andanelectrophiliccarbon.[1]Despitethewellestablishedexperimentalpractice,themoleculardetailsofsuchreactionsarenotwellunderstoodyet.TheseveralissuesrelatedtoGrignardreagentscomprisetheaggregationstatesoftheR-Mg-Xmolecules,thepossibleco-existenceofmultiplestructuresforsuchaggregates,aswellasthecoordinationchemistryoftheinvolvedMg2+ions.Ourstudyinvolvesab-initiomoleculardynamics,wheretheelectronicproblemissolvedbyDensity-Functional-Theory[2]usingthePerdew-Burke-Ernzerhofexchange-correlationfunctional.[3]Enhancedsamplingoftheconformationalspaceisachievedbymetadynamicssimulations.[4]Ourresultsshowthatvariouscompoundsthatarecharacterisedbydifferentsolvationstructuresarethermallyaccessible.Inparticular,allstepsleadingtothe(CH3MgCl)2=Mg(CH3)2+MgCl2reaction(Schlenkequilibrium)aredirectlycontrolledbythedynamicsofTHFmolecules,whichactbothasbothnucleophileandleavinggroupsattheMg2+centre.Therefore,understandingreactivityofGrignardreagentsrequirestakingintoconsiderationsolventmoleculesasdirectcomponentsofthereactionpathwaysaswellasmultipleconformationsandsolvationstructures.

References

[1]Shirley,D.A.Org.React.8:28–58.(1954).

[2]Lippert,Gerald;Hutter,Jürg;Parrinello,MicheleTCA:Theory,Computation,andModeling103(2):124–140.(1999).

[3]Perdew,JohnP.;KieronBurke;MatthiasErnzerhofPhys.Rev.Letters77(18):3865–3868.(1996).

[4]Laio,A.;Parrinello,M.PNAS99(20):12562–12566.(2002).

ISQBPPresident’smeeting2016–19-22June

Topic:Other

P21:AtomisticSimulationofSolubilizationofPolycyclicAromaticHydrocarbonsinaSodiumDodecylSulfateMicelle

X.J.Liang*[1-3],M.Marchi[2-3],S.Abel[2-3]

[1]SchoolofEnvironmentandEnergy,SouthChinaUniversityofTechnology,China

[2]Commissariatàl'EnergieAtomiqueetauxEnergiesAlternatives,DRF/IBITECS/SB2SM/LBMS&CNRSUMR9198,Saclay,France

[3]InstituteforIntegrativeBiologyoftheCell(I2BC),CEA,CNRS,UnivParis-Sud,UniversitéParis-Saclay,91198,Gif-sur-Yvettecedex,France

Surfactant-enhancedsoulubilizationofpolycyclicaromatichydrocarbons(PAHs)hasbeenconsideredasapromisingtechniqueforwaterandsoilremediation.OneofthemainfactorsaffectingremediationefficiencyissurfactantsoulubilizationpowertowardsPAHs,whichdependson

soulubilizationsitesofPAHsinthemicelle.Hence,tocapturethesoulubilizationsitesattheatomiclevel,solubilizationoftwoPAHs,naphthalene(NAP,2-benzene-ringPAH)andpyrene(PYR,4-benzeneringPAH),intoasodiumdodecylsulfate(SDS)micellewasdonethrough

all-atommoleculardynamics(MD)simulations.WefindthatNAPaswellasPYRcouldmovebetweenthemicelleshellandcoreregionscontributingtotheirdistributioninbothregionsofthemicelleatanyPAHconcentration.Moreover,bothNAPandPYRprefertostayinthemicelle

shellregion,whichmayarisefromthegreatervolumeofthemicelleshell,theformationofhydrogenbondsbetweenNAPandwaterandthelargermolecularvolumeofPYR.ThePAHsareabletoformoccasionalclusters

(fromdimertooctamer)insidethemicelleduringthesimulationtime,dependingonPAHconcentrationinthesolubilizationsystems.Furthermore,themicelleproperties(i.e.size,shape,micelleinternalstructure,alkylchainconformationandorientation,andmicelleinternaldynamics)arefoundtobenearlyunaffectedbythesolubilizedPAHs,whichisirrespectiveofthepropertiesandconcentrationsofPAHs.

ISQBPPresident’smeeting2016–19-22June

Topic:Other

P22:Coarse-grainedmoleculardynamicsoftheionicflowthroughaproteicnanopore

RosaRamirez[1],NathalieBasdevant*[1]

[1]LAMBELaboratory,UniversityofEvry,France.

Coarse-grainedmodels,whichrepresentseveralatomsbyonesite,arebecomingincreasinglypopularsincetheycanovercomethelimitationsofall-atommodelstosimulatemoleculardynamicsofbiologicalsystemsfortime-lengthsclosertoexperiments.

Wehaveperformedcoarse-grainedmoleculardynamics,usingtheMARTINIforce-field,oftheionictransportthroughaproteicnanopore,thealpha-hemolysinchannel,insertedintoaDPPClipidmembranebilayersurroundedbysolventandKClions,inthepresenceofdifferentelectricfields.Thesystem,composedof360000atoms,isreducedto90000coarse-grainedsites,allowingmoleculardynamicsofseveralmicroseconds.Thistime-lengthisclosertothecharacteristictimeofthenanoporeexperimentswhicharealsoconductedattheLAMBE.

Usingthesesimulations,wehavecomputedioniccurrentsthroughtheporeconsistentwithexperiments.Inparticular,wecouldobservedtheso-called"rectification”,whichisthecurrentasymmetrybetweenpositiveandnegativefields,accordingtopreviousstudiesandexperiments.Thisasymmetrycouldbeexplainedbystudyingtheionicdistributionaroundthepore.Additionalsimulationsofanon-chargednanoporeatthesameconditionsgaveusinsightabouttheroleoftheporegeometryinthisasymmetry.

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P23:NorovirusCapsidAssembly

ThibaultTubiana*[1],AnnaD.Koromyslova[2,3]GrantSHansman[2,3],YvesBoulard[1],StéphaneBressanelli[1]

[1]Interactionsandassemblymechanismsofproteinsandpeptides,B3S,I2BC,UMR9198

[2]SchallerResearchGroupattheUniversityofHeidelbergandtheDKFZ,Germany,Heidelberg69120

[3]DepartmentofInfectiousDiseases,Virology,UniversityofHeidelberg,Germany,Heidelberg69120

Norovirusesaresmallnon-envelopedviruseswithsingle-strandedpositivesenseRNA.Theyaretheleadingcauseofacuteviralgastroenteritisinhumansandanimalsandareofworldsignificanceforhealth.TheCapsidiscomposedof180copiesofasinglestructuralproteinVP1consistsoftwomaindomains:theshelldomain(S)andtheprotrudingdomain(P)whichcontainstwosubdomains(P1andP2).ThePdomainisthepartexposedtothebiologicalenvironment,itallowsinparticulartostabilizeandadjustthesizeofthecapsid.TheSdomainis,meanwhile,theassemblymoduleofviralcapsid.

OurlabandothershaveshownexperimentallythatNoroviruscapsidscanbedisassembledandreassembledinvitroaccordingtothepHofthemedium(highpH=disassembled,lowpH=reassembled).TheassemblyprocessbeginswithVP1dimerswhichquicklyproduceintermediatesof10~11dimerswhichthenslowlyassemblethemselvestocapsids.

Usingcomputationalapproachessuchashomologymodelling,simulatedannealing,moleculardynamicssimulationsinallatomandcoarsegrainsystems,wearelookingtoextendtheseskineticstudiesonhumannorovirusandthustodeterminethemolecularbasisofnoroviruscapsidassembly.

Ourfirstresultsextendpreviousstudiesalreadyachievedintheteam.ThesesresultsshowthatthedeprotonatedformoftheN-terminalarmestablishesmanysaltbridgesandallowitsstabilizationontheSdomain.OurnewSAXSexperimentsshowthatathighpHthedimerisinaquiteextendedformandverydifferentfromthecrystallographicstructure.ThankstomodelisationandmoleculardynamicstoolswehavedevelopedamodelthatfitstheexperimentalSAXSdata.OurresultsindicatethatpHandprotonationstatehaveamajorroleinthefirststepofassembly:Dimertointermediate.

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P24:MoleculardynamicssimulationsofcytosolicphospholipaseA2incomplexwithpotentinhibitors

S.Vasilakaki[1],T.Mavromoustakos[1],G.Kokotos*[1]

[1]DepartmentofChemistry,NationalandKapodistrianUniversityofAthens,Greece

PhospholipasesA2(PLA2s)isasuper-familyofenzymesthatcleaveafattyacidfromthesn-2positionofphospholipids.Theproductsofthisenzymaticreactionpromotetheappearanceofinflammatoryevents.Thecurrentresearchinthisfieldtargetstoidentifytheconditionsthatpromotetheupregulationoftheseenzymesandthecross-correlationbetweentheisoforms.However,boththehighhomologyoftheenzymesbelongingtothesamegroupandtheirsimilarcatalyticmechanism,makethistargetchallenging.

TherearesixgroupsofPLA2andeachofthemconsistsofmanysubgroups.HerewepresentourcomputationalstudiesoncytosoliccPLA2groupGIVAincomplexwiththreepotentinhibitors.Theenzymehasbeencrystallizedintheunboundstateandflexibledockingwasusedinordertoplacetheinhibitorsintheactivesite.InordertodetermineastandardmethodofsimulatingthecPLA2complexes,producingfastandcleanresults,wesimulatedtheknownpyrrophenone[1]inhibitorandtwohighlypotentcPLA2inhibitors,56n[2]andAX074[3].BindingfreeenergycalculationswereperformedusingtheMM-PBSAmethodandprincipalcomponentanalysisusingthecpptrajmoduleofAmberTools.

Acknowledgments:

‘Thisresearchhasbeenco-financedbytheEuropeanUnion(EuropeanRegionalDevelopmentFund-ERDF)andGreeknationalfundsthroughtheOperationalProgram‘‘CompetitivenessandEntrepreneurship’’oftheNationalStrategicReferenceFramework(NSRF)-ResearchFundingProgram:“PhospholipasesA2inhibitors:Developingadrugpipelineforthetreatmentofinflammatoryneurologicaldisorders."

‘ThisworkwassupportedbycomputationaltimegrantedfromtheGreekResearch&TechnologyNetwork(GRNET)intheNationalHPCfacility“ARIS”underprojectID:pr001008-COMPINFLAM.’

References

[1]Burke,J.E.etal.J.Am.Chem.Soc.2009,131,8083–8091

[2]Tommo,T.etal.J.Med.Chem.2014,57,7244–7262

[3]Stephens,D.etal.J.Med.Chem.2006,49,2821-2828

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P25:ComparativeanalysisofproteinflexibilityusingtheWEBnm@v2.0

S.P.Tiwari*[1,2,5],E.Fuglebakk[1,2],S.MHollup[2],L.Skjaerven[2,3],T.Cragnolini[1,2,4],S.H.Grindhaug[2],K.M.Tekle[2],ReuterN.[1,2]

[1]DepartmentofMolecularBiology,UniversityofBergen,Norway

[2]ComputationalBiologyUnit,DepartmentofInformatics,UniversityofBergen,Norway

[3]DepartmentofBiomedicine,UniversityofBergen,Bergen,Norway

[4]Presentaddress:UniversityChemicalLaboratories,UniversityofCambridge,UnitedKingdom

[5]Presentaddress:ComputationalStructuralBiologyResearchUnit,RikenAdvancedInstituteforComputationalScience,Kobe,Japan

Thescopeforexploringthedynamicallandscapesofproteinsincreaseswithincreasingavailabilityofstructuraldata.Oneapproachinvolvesthecomparisonoftheintrinsicflexibityofproteins,wherechangesthattakeplaceduetomutationsthatimpactfunctionortheirevolutionaryconservationcanbeanalysed.Normalmodeanalysis(NMA)usingelasticnetworkmodels(ENMs)hasbeenshowntobeaneffectivecomputationalmethodtostudytheintrinsicflexibilityofproteins,anditsefficiencymakesitwell-suitedforanalysinglargerdatasets.WeprovideaccesstoarobustcomparativeanalysisprotocolinWEBnm@v2.0(http://apps.cbu.uib.no/webnma/home)thatisquickandeasytorun,requiringthealignmentofthestructuraldatasetintheFASTAformatandtheirPDBfilesasinput(Tiwarietal.,2014).TheprotocolincludestheimplementationoftheBhattacharyyacoefficient,ascorethathasbeenshowntobeareliablesimilaritymeasurebetweenpairsofproteinsinadataset(Fuglebakketal.,2012,Fuglebakketal.,2013,Pericaetal.,2014).Wehaveupgradedtheweb-interfacetoimproveitsusabilityandperformances,suchasincludingtheinteractivevisualisationofthesixlowestenergynormalmodevectorsandtheanalysisofpairwisecorrelations.Inadditiontotheupdates,wehavealsoprovidedaSOAPweb-serviceforamoreprogrammableinterfaceforbothofthesesections.

[1]TiwariS.P.,FuglebakkE.,HollupS.M.etal.(2014)BMCBioinform.15:427

[2]FuglebakkE.,EchaveJ.,ReuterN.(2012)Bioinformatics28(19):2431-2440

[3]FuglebakkE.,ReuterN.,HinsenK.(2013)J.Chem.TheoryComput.9(12):5618-5628

[4]PericaT.,KondoY.,TiwariS.P.etal.(2014)Science346(6216):1254346

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P26:FoldandFlexibility:Whatcanproteinsmechanicalpropertiestellusabouttheirfoldingnucleus?

S.Sacquin-Mora*[1]

[1]LaboratoiredeBiochimieThéorique,CNRSUPR9080,InstitutdeBiologiePhysico-Chimique,13

ruePierreetMarieCurie,75005Paris,France

Thedeterminationofaprotein’sfoldingnucleus,i.e.asetofnativecontactsplayinganimportant

roleduringitsfoldingprocess,remainsanelusiveyetessentialprobleminbiochemistry.Inthis

work,weinvestigatethemechanicalpropertiesof70proteinstructuresbelongingto14protein

familiespresentingvariousfoldsusingcoarse-grainBrownianDynamics(BD)simulations.The

resultingrigidityprofilescombinedwithmultiplesequencealignmentsshowthatalimitedsetof

rigidresidues,whichwecalltheconsensusnucleus,occupyconservedpositionsalongtheprotein

sequence.Theseresidues’side-chainsformatightinteractionnetworkwithintheprotein’score,

thusmakingourconsensusnucleipotentialfoldingnuclei.Areviewofexperimentalandtheoretical

literatureshowsthatmost(above80%)oftheseresidueswereindeedidentifiedasfoldingnucleus

memberinearlierstudies.

Keywords:proteinfolding;foldingnucleus;proteinsmechanics;coarse-grainsimulations.

Ref:Sacquin-Mora,J.Royal.Soc.Interf.,12:20150867,2015

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P27:DesigningpeptideligandstoinhibittheTiam1PDZDomain

N.Panel*[1],T.Simonson[1]

[1]BiochemistrylaboratoryofEcolePolytechnique,UMR7654,France

Small,modularproteindomainsoftendirectprotein-proteininteractions(PPIs)andformthebuildingblocksofeukaryoticsignallingpathways.PDZdomainsareamongthemostwidespreadandbest-studied,withover400inourgenome.Theyspecificallyrecognizethe4-7C-terminalaminoacidsoftheirtargetproteins,aswellasthecorrespondingpeptidesinisolation.WefocusontheTiam1protein,aRacGTPexchangefactorinvolvedinneuronalprotrusionandaxonguidance.ItsactivitymodulatesRacsignaling,whosedysregulationcancausecancer.Tiam1canbeinhibitedbysmallpeptidesthatbindtoitsPDZdomainanddownregulateitsinteractionwithitstargetproteins,includingRac1.InhibitionofPPIsiscurrentlyadifficultbutrecognizedstrategyfordrugandbioreagentdesign.

ToinvestigatetheTiam1-peptidebindingmechanismanddiscoverpotentialpeptideinhibitors,structuralmodelswerebuiltandMDsimulationsdoneforover40Tiam1-peptidecomplexes,basedonavailablecrystallographicstructures.Thepeptidesequencesincludedexperimentally-studiedvariantsofthenaturaltargetligandsyndecan,sequencesfromacombinatoriallibraryofpeptidebinders,andvariantswithnewsidechaintypesatthemainspecificitypositions(thelastfourpositionsofthepeptide).BindingfreeenergydifferenceswerecomputedusingbothPoisson-BoltzmannandGeneralizedBorncontinuumelectrostaticsmodels,combinedwithasimpleLinearInteractionEnergyfreeenergyfunction.Forafewofthevariants,morerigorous,alchemicalMDfreeenergysimulationswereperformed,providingreferencedata.Allthesesimulationsleadtosimplebutwell-parameterizedPB/GBmodelsanddatasetsthatrepresentanimportantbenchmarkforthisleveloftheory.Theyalsogivedetailedinsightsintothegroupsandinteractionsthatdetermineprotein-peptidebinding,andshouldhelpustodiscoververytightlybindingpeptidesandpeptidomimeticsforuseasbioreagents

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P28:ThermodynamicsofProteaseSubstrateSpecificity

U.Kahler,B.Waldner,JulianE.Fuchs,KlausR.Liedl*

UniversityofInnsbruck

Proteasesshowabroadspectrumofspecificityfromveryspecificproteaseswithuniquecleavagepatternsinvolvedincellularsignalingpathwaystopromiscuousproteasesthattakepartindigestiveprocessesandcleaveawiderangeofsubstrates.

Weaimatunderstandingmechanismsofproteaserecognitionandexplainingthedifferencesintheirspecificity.Inourgroupametrichasbeendevelopedthatquantifiesthesub-pocket-wisespecificityofproteasesbasedontheexperimentalcleavagedataintheMEROPSdatabase.

Specificityislinkedtothelocalflexibilityofthebindingsiteregionsoftheproteases.Variousinteractionsbetweenproteinandsubstrateparticipateinbinding.Bothenthalpicandentropictermsinfluencesubstraterecognitionandareestimatedbymoleculardynamicssimulationsofserine,cysteineandasparticproteases.Theflexibilityoftheproteasesisassessedwithdifferentmetrics.Oneofthem,dihedralentropies,usesthestatepopulationsofdihedralsintheproteasebackboneoversimulationtimetoquantifylocalresidue-wisebackboneflexibility.Therebyitisalignment-independentunlikethemeansquarefluctuationandtheB-factor.LocalinteractionpotentialsareevaluatedwithGRID.Itcalculatesallmajorenthalpicinteractionsthatcancontributetosubstratebinding.GRIDisnotonlybeusedontheX-raystructuresbutalsoonrepresentativestructuresfromtheMDsimulationclusters.

Furthermorehydrationcontributestoproteinrecognition.Rotationalandorientationalentropiesofwaterorderingaswellassolute-solventandsolvent-solventinteractionsoverthecourseofthetrajectoryarecalculatedwiththeGISTalgorithm.Thus,theimpactofsolvationonsubstratebindingisinvestigated.

Thedeterminedentropicandenthalpiccontributionstosubstraterecognitionareusedtoexplaintheexperimentallymeasuredsubstratereadoutofproteases.

Theinformationonthedrivingfactorsofsubstraterecognitioncanbetransferredtosmallmoleculesandprovideaccesstonew,moreefficientstrategiesfordrugdesignprocesses.

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P29:SpecificitydeterminantswithintheBcl-2familyrevealedbydynamicsandenergetics

S.Ivanov*[1,2],R.Huber[1],J.Warwicker[2],P.Bond[1,3]

[1]BioinformaticsInstitute,AgencyforScience,TechnologyandResearch(A*STAR),Singapore

[2]ManchesterInstituteofBiotechnology,TheUniversityofManchester,UK

[3]DepartmentofBiologicalSciences,NationalUniversityofSingapore,Singapore

Geneduplicationisoneofthemoreprevalentmechanismsintheexpansionanddiversificationofproteinfamilies,leadingtoanabundanceofintra-andinterfamilyprotein-proteininteractionsincriticalregulatorynetworks.Subsequenttogeneduplication,bindingspecificitycandivergeatgreatlydifferingrates.Quiteoften,potentialbindingpartnersarehighlysimilarwithonlysubtledifferencesbetweenbindersandnon-binders.Thus,elucidatingandpredictingthespecificitydeterminantswithinthesesystemsbecomesadaunting,yetpressingtask.

Here,wepresentamoleculardynamics-basedenergeticanalysisoftherecognitionmechanismandspecificitydeterminantswithintheBcl-2familyofapoptosis-regulatingproteins–acentralnodeintheintrinsicapoptoticpathway.Duetotheirapoptosis-regulatingfunction,theseproteinsareintenselyinvestigatedtargetsforanticancertherapeutics.Beingguidedbyacomprehensivedatasetofisothermaltitrationcalorimetrybindingdata,wefirstmodeledatotalof60differentcomplexescomprisingfiveantiapoptoticproteinsboundtodifferentBH3peptideswithaffinitiesspanningfourordersofmagnitude.Subsequently,usingtheAmber14packageandff14SBforcefield,wegeneratedextensive,atomic-resolutionsimulationsamplingforeachcomplex,totaling~20microsecondsofconformationaldynamics.Wequantitativelyassessedtheenergeticsoftheprotein-proteininteractionsacrosstheentirefamilyviamolecularmechanics/PoissonBoltzmannsurfacearea(MM/PBSA)calculations.Finally,bymappingthemeansandvarianceofthecomputedper-residueΔHvaluestotheproteinmolecularsurface,weelucidatethemechanismunderlyingintermolecularrecognitionwithinthefamily,demonstratewhereaffinityandspecificityarise,andsubstantiateourresultswithextensiveexperimentalevidence.Ourworkhasconsiderableexplanatorypowerwithregardtoexperimentalobservations.Moreover,ourresultsofferin-depthinsightintotherelationshipbetweensequence,energetics,andstructure-wedemonstratethatintheBcl-2family,foldsaremoreconservedthanenergies,whichareinturnmoreconservedthansequences.Wealsoelucidateenergyandspecificityhotspots,whichshouldhelpguidethedesignoftargetedtherapeuticswithdesiredbindingcharacteristicsformanipulatingtheprotein-proteininteractionswithintheapoptosis-regulatingpathway.Critically,theapproachtakenheremayrepresentageneralmethodologyfortargetingotherparalogousprotein-proteininteractions.

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P30:Ahybridparticle-fieldmodelforcoarse-grained/mesoscalesimulationsofpolypeptides

SigbjørnL.Bore,[1]HimaB.Kolli,[1]GiuseppeMilano,[2]andMicheleCascella[1]

[1]DepartmentofChemistryandCentreforTheoreticalandComputationalChemistry,UniversityofOslo,Norway

[2]DepartmentofChemistry,UniversityofSalerno,Italy

TheHybridparticle-field(MD-SCF)methodhasproventobeapowerfultoolinthestudyofsoftmattersystems.[1]Inthismethodnon-bondedinteractionsaretreatedinameanfieldformalism.Computationalefficiencyisgainedbyavoidingpairinteractionsandisefficientlyparallelizable.[2]HerewepresenttheextensionofMD-SCFtostudypolypeptidechains.Ourmodelisbasedonatwo-beadcoarsegrainedrepresentationofaminoacids,andexplicitelectrostaticsfollowingthemultipolarreconstructionmethodpreviouslyestablished.[3]Thenewmodelpresentsanaccuratecalibrationofbondedinteractionsforthebackbonebyacombinedbendingandtorsionalpotential.Thereferencepotentialofmeanforce(PMF)isobtainedfrommetadynamicssimulationsofanatomisticmodelofpolyglycineinwater.Stabilizationofsecondarystructuresbyhydrogenbondsarereproducedbydipole-dipoleinteractions.Theimplementedalgorithmrigorouslydistributesforcesactingonthepeptidedipolesontothebeads,thusnotenlargingthenumberofdegreesoffreedomofthesystem.Aminoacidstructuralpropensityisintroducedbyappropriatetorsionalpotentialsbetweenbeads.ThemodelisimplementedinOCCAM,ahybridMDandfieldsimulationpackage.[2]Thenewimplementedmodelswillpromoteefficientstudyofproteindynamicsinverylargesystems.

ISQBPPresident’smeeting2016–19-22June

Topic:Proteindynamics

P31:UNRAVELINGTHEINHIBITORYMECHANISMOFALPHA-1ANTITRYPSINUSINGACCELERATEDMOLECULARDYNAMICS

O.J.Andersen*[1,2],M.W.Risør[1,3,4],E.C.Poulsen[1,3],N.C.Nielsen[1,2],Y.Miao[5],J.J.Enghild[1,3],B.Schiøtt[1,2]

[1]CenterforInsolubleProteinStructures(inSPIN)andtheInterdisciplinaryNanoscienceCenter(iNANO),AarhusUniversity,Aarhus,Denmark

[2]DepartmentofChemistry,AarhusUniversity,Aarhus,Denmark

[3]DepartmentofMolecularBiologyandGenetics,AarhusUniversity,Aarhus,Denmark

[4]DepartmentofIntegrativeStructuralandComputationalBiology,TheScrippsResearchInstitute,LaJolla,CA92037,UnitedStates

[5]HowardHughesMedicalInstituteandDepartmentofPharmacology,UniversityofCaliforniaatSanDiego,LaJolla,CA92093,UnitedStates

Background:Alpha-1antitrypsinisaserineproteaseinhibitor(belongingtotheserpinsuperfamily)thatprotectslungtissuefromdegradationbyhumanneutrophilelastase[1].Itsstructurecontainsastretchofaminoacidsknownasthereactivecenterloop(RCL)thatactsasasubstratefortheprotease.Aspartoftheproteasecleavagemechanism,anacyl-enzymeintermediateisformedbetweentheproteaseandtheRCL.Beforethecleavagecanbecompleted,aconformationalchangeoccursinwhichtheproteaseistranslocatedfromthetoptothebottomofantitrypsin[2],duringwhichtheactivesiteoftheproteaseisdistortedtosuchanextentthatthecomplexgetstrappedintheacyl-enzymeintermediatestate.Antitrypsinthusactsasasuicideinhibitoragainsttheprotease.Concomitantlywiththetranslocationoftheprotease,theRCLisinsertedasanextraβ-strandinthecentralβ-sheetofantitrypsin.Themechanismbehindthisinsertionprocessisoneofthegreatmysteriesofserpinfunction.Tocomplicatethematter,ahelixisplacedinfrontofthesheet,seeminglyobstructingtheinsertion.

Findings:BasedonatrajectoryoftheRCLinsertionprocessobtainedusingacceleratedmoleculardynamics,wesuggestthatthehelixplacedinfrontofthecentralβ-sheetactsasachaperonethatacceleratestheinsertion.ItdoessobyreducingtheconformationalspacereadilyavailabletotheRCLbyformingstableinteractionswithitthroughouttheentireinsertionmechanism.AnotherconundrumstemsfromtheconversionoftheRCLintoaβ-strand,whichentailsthateveryotherresiduemustinsertintotheproteincore.Theobtainedtrajectoryrevealshowthisisenabledbyinternalwaterpocketsandpathwayswithintheprotein.

[1]Gooptu,B.,Lomas,D.A.J.Exp.Med.7(2008)1529-1534

[2]Huntington,J.A.TRENDSBiochem.Sci.31(2006)427-435

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P32:MappingofCholesterolBindingSitessurroundingTheHumanDopamineTransporter

TaliaZeppelin*[1],XavierPeriole[1]andBirgitSchiøtt[1]

[1]DepartmentofChemistry,AarhusUniversity,Denmark

Thehumandopaminetransporter(hDAT)isessentialforregulatingdopaminergicneurotransmissionbytransportingdopaminefromthesynapticcleftbackintothepresynapticneuron.DysregulationofhDATisinvolvedinseveraldebilitatingdiseasessuchasParkinson'sdisease,attentiondeficithyperactivedisease(ADHD)andTourette'ssyndrome,amongothers.DATisalsothetargetofmanyillicitdrugsandhasbeenpresumedtobeinvolvedinthedevelopmentofaddiction.Itisthereforeessentialtofurthertheunderstandingofthetransportersarchitecture,transportmechanismandmeansofregulationtoaidindrugdevelopment.TherehasbeenpublishedarangeofDATstructuresallfromthespeciesDrosophiliaMelanogaster,whichcontainatleastoneconservedco-crystallizedcholesterolmolecule.ItisbelievedthatcholesterolactsinregulatinghDATactivity,butwhetheritsmechanismofregulationissitespecific,hasyettoberesolved.Thisquestionissoughttobeansweredwithinthiscontributionusingcoarse-grainedmoleculardynamicssimulationsofahDAThomologymodelembeddedinamixedPOPCandcholesterolmembrane.BasedonpreliminaryresultsitseemsthatthereexistscholesterolspecificsitessurroundinghDATandthatonepredominatesovertheothersinoccupancyduringthesimulation.

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P33:ComputationalinvestigationofthemembraneassociationofN-terminalacetyltransferase60(Naa60)

Q.Waheed*[1],N.Reuter[1]

[1]DepartmentofMolecularBiology,UniversityofBergen,Norway

N-terminalacetyltransferases(NATs)aremembersofGCN5-re-latedN-acetyltransferase(GNAT)superfamily,knownforplayingcatalyticroleinN-terminalacetylationoftheproteins.VeryrecentexperimentalstudieshaveshownthatNatForNa-acetyltransferase60(Naa60)istheonlymemberofthisfamilywhichgivesevidenceoforganellarsub-cellularlocalization.Theothermembershavebeenshowntolocalizeinthecytosole.Furthermore,Naa60knockdowncausesGolgiscattering,indicatingthatitplaysimportantroleinGolgiintegrityandlocalizetoGolgi.ItisalsoshownexperimentallythatonlytheC-terminalpartoftheproteinisimportantandenoughforitsmembraneassociation.

Wehaveusedmoleculardynamic(MD)simulationstostudythemembraneassociationofNaa60.Implicitandcoarsegrainedmodelsgiveopportunitytostudythelongtimephenomenonlikeproteins-membranesbinding.PredictedsecondarystructurehavingtwohelicesintheC-terminalregionofNaa60wasusedforsimulations.Helicalwheelanalysisofboththehelicespredictstronghydrophobicfaces.MDsimulationsshowthathelicesbindwiththemembranethroughthehydrophobicinteractionsandthebindingmodeoftheC-terminalofNaa60isperipheral.

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P34:InvestigatingtheInteractionofthePutativeTransmembraneDomainofHumanPhospholipidScramblasewithLipidBilayersusingMolecularDynamicsSimulations

T.Venken[1],A.Schillinger[1],E.Fuglebakk[1],N.Reuter[1]

[1]DepartmentofMolecularBiology,UniversityofBergen,Norway

Humanphospholipidscramblase1(SCR)containsaC-terminalhelix(CTH)(residues288-318)thathasbeenpredictedtobeatransmembranedomain.Surprisingly,theCTHsequencecontainsanaspartate,aresiduecommonlynotfoundintypicaltransmembranesegments.Toexplainthisdiscrepancy,weappliedamultiscalemodellingapproachusingimplicit,coarse-grainedandatomisticmoleculardynamicssimulationstoinvestigatethedynamicsoftransmembraneCTHinlipidbilayers.Twopeptidesweretested,onecontainingtheputative19aminoacidtransmembranesegmentofSCRandalongerconstructcontainingalsothesubsequentC-terminalend.Wefindthat,althoughtheAspcaninducelocalwaterdefectsfortheshortestpeptide,thedefectsareminorforthelongestpeptideandarereducedevenfurtherwhencholesterolispresentinsidethemembranemodels.TheC-terminalresiduesoftheCTHengageinspecificpolarinteractionswiththecholesterolhydroxylgroup,inagreementwithpreviousexperiments.Notably,weshowthattheAspisalsoimportantfortherecognitionofcholesterolmoleculesandhencecontributestothestabilizationofthepeptidewithinthemembrane.ThisstudysupportstheideaoftheCTHasatransmembranesegmentandexplainsthemolecularrecognitionofcholesterolbytheSCRC-terminalend.WespeculatethatprotonationofC-terminalacidicresiduescanbeimportantformodulatingthesizeofthewaterdefects,therebypossiblyinfluencingtheSCRscramblingactivity.

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P35:Interactionofsmallmoleculeswithlipidbilayers.

E.Sanchez-Garcia[1],S.Mittal*[1]

[1]DepartmentofTheoreticalChemistry,Max-Planck-InstitutfürKohlenforschung,Mülheimander,Germany

Biologicalmembranesaredynamicstructuresthatfacilitateimportantfunctionsinthebody,suchascontrollingthemovementofvarioussubstancesacrossthecell.Thehumanimmunodeficiencyvirus(HIV-1)isanenvelopedretrovirus,whichacquiresitslipidenvelopeprimarilyfromthehostcellmembraneitfusesto.ItiswelldocumentedthatthelipidenvelopeofHIV-1isenrichedincholesterolandsphingomyelin,amongotherlipids.[1]

ThemoleculartweezerCLR01isasupramolecularligandthatfeaturesabelt-likeelectron-richcavityformedbyalternatingfusednorbornadieneandbenzenerings.CLR01isabletobindspecificallytolysineand,tolesserextent,toarginineresiduesviacombinedhydrophobicandelectrostaticinteractions.MoleculartweezershavebeenreportedtomodulatepropertiesofproteinssuchashIAPP,α-synucleinandPAP248-286,withpotentialtherapeuticimplicationsforthetreatmentofdiseaseslikeDiabetesII,ParkinsonandHIV,amongothers.[2-4]

Here,weusemoleculardynamicssimulationstoinvestigatethemechanismofmembranedisruptionbyCLR01inlipidbilayermodels.Asacontrolsetup,wealsostudytheinteractionsofCLR03,areferencemoleculecarryingthesamechargedcorethanCLR01butlackingitselectron-richcavity.

References:

1.Aloia,R.C.,etalProc.Natl.Acad.Sci.U.S.A.85,900(1988).

2.Fokkens,M.,Schrader,T.,Klärner,F.-G.J.Am.Chem.Soc.127,14415(2005).

3.Lopes,D.H.J.etalACSChem.Biol.10,1555(2015).

4.Lump,E;etalelife,4:e05397(2015).

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P36:Peripheralmembranebindingwithprotrudinghydrophobes

E.Fuglebakk*[1,2],N.Reuter[1,2]

[1]ComputationalBiologyUnit,UniversityofBergen,Norway

[2]DepartmentofMolecularBiology,UniversityofBergen,Norway

Manyimportantbiologicalprocessesoccurattheboundariesofcellsandorganelles,namelyatcellmembranes.Importantfunctionslikesignalling,recognition,traffickingandcelldivisioninvolveproteinsinteractingwithmembrane.Inalloftheseprocessesperipheralmembraneproteinsarefoundtoplayarole.Peripheralmembraneproteinsaresolubleproteinsthatbindthemembraneshallowlyandoftentransiently.Hencetheirsurfacearequitesimilartothoseofglobularsolubleproteins,andidentificationandrationalisationoftheirinterfacialbindingsitesisnotstraightforward.Wehavedefinedstructuralcharacteristicsthatfacilitatemembraneinteractiononperipheralproteins,andcomparedthesurfacesofperipheralmembraneproteinswithproteinsurfacesnotinteractingwithmembrane.Inparticularweuseacoarsegrainedrepresentationoftheproteinsurface,toidentifystructuralprotrusionsthatexposehydrophobicresidues.Ourstatisticalanalysisallowsustocomparethesurfacesofbindingandnon-bindingproteins,withoutknowingtheexactinterfacialbindingsiteoftheperipheralbinders.Thisallowsustoextendouranalysisbeyondthesmallsetofexperimentallyverifiedbindingsites,toalargesetofproteinsclassifiedasperipheralmembranebinders.Fromthisanalysiswecanconfidentlyconcludethatprotrudinghydrophobesareover-representedonperipheralmembranebinders,thattheytendtoclusterinpositionsthatareco-insertabletothemembrane,andthattheyarepreferentiallylocatedonbothexperimentallyverifiedbindingsites,andbindingsitespredictedbyothercomputationalapproaches.Wefindthatoursimplemodelisabletopartlyexplainthemembraneinteractionofmostknownperipheralmembranebinders.Thewellknownaliphatichelicesoninterfacialbindingsitesarespecialcasesofprotrudinghydrophobes,andwebelievethatourgeneralisationofthisconceptprovidesconditionsformembraneinteractionthatwillbeveryusefulforanyoneinterestedinunderstanding,predictingordesigninginterfacialbindingsitesonproteins.

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P37:Fullinsilicofoldingofanamphipathichelixinthewater/membraneinterface

AmélieBâcle[1],LydieVamparys[1,2],JérémyEsque[3],GuillaumeDrin[4],CatherineEtchebest[2],PatrickFuchs*[1]

[1]Dynamiquedesmembranesettraficintracellulaire,InstitutJacquesMonod,CNRSUMR7592,UniversitéParisDiderot,SorbonneParisCité,15rueHélèneBrion,75013Paris

[2]INSERMUMR-S665,équipeDSIMB,UniversitéParisDiderot,SorbonneParisCité,InstitutNationaldeTransfusionSanguine,6rueAlexandreCabanel75739ParisCedex15,France

[3]Biocomputinggroup-StructuralBiology&GenomicsDept.–IGBMC,CNRSUMR7104-INSERMU964,1rueLaurentFries67404Illkirch-GraffenstadenCedex,France

[4]InstitutdePharmacologieMoléculaireetCellulaire,UMRCNRS7275,660,routedeslucioles,06560ValbonneSophia-Antipolis

Amphipathicalpha-helices(AHs)areubiquitousstructuralmotifsinlivingorganismsthathaveavarietyoffunctions.Forexample,AHsfromantimicrobial/venompeptidescanmakeporesinmembranes.PeripheralproteinscanreachspecificcellularcompartmentsthankstoAH(s)withintheirsequencethatselectivelysensespecificlipidcompositions.Usually,AHsaresolubleandunfoldedinwatermediaandgetfoldeduponbindingwithinthemembranewater/interface.Fromanenergeticpointofview,thisfoldingprocessplaysacrucialroleforthebindingaffinity,theselectivityofAHsformembraneandultimately,fortheirfunction.However,thisfoldingprocesshasbeensofarpoorlyunderstoodanddescribedattheatomisticlevel.Hereweusereplica-exchangemoleculardynamics(REMD)simulationstogetinsightsintotheinsertion/foldingofavenompeptide,Mastoparan-L,atthesurfaceofaflatphospholipidmembrane.Thisapproachallowsustoobservemanyhelixfolding/unfoldingeventswithexplicitatomicdetails.ThebindingofMastoparan-Lproceedssystematicallybypeptideinsertionwithinthemembranefollowedbyinterfacialhelixfolding.Thefoldingresultsfromanucleation/propagationmechanismgenerallyfromtheN-totheC-terminus.Furthermore,weevaluatetheenergeticcostofformingacavitywithinthelipidstoaccommodatethehelix.Thiscostconsiderablyslowsdownthefoldingkineticscomparedtothatinanaqueousenvironment.CDexperimentsofMastoparan-Linpresenceoflargeliposomesrevealahighhelicity,similartothatpredictedbyourREMD.Jointly,theseresultsindicatethatourREMDapproachissuccessfulforsimulatingthefullfoldingofanAHwithintheinterfaceenvironmentandgiveunprecedentedquantitativeresultsinagreementwithinvitroexperiments.OurworkpavesthewaytoabetterunderstandingofAHsselectivityforcellularmembranes,andshowsthatpredictinginsilicotowhichspecificmembranesanAHbindsiswithinreach.

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P38:ModellingAmylinSelf-assembly

M.Christensen*[1,2],K.K.Skeby[1],B.Schiøtt[1,2]

[1]DepartmentofChemistry,UniversityofBergen,Norway

[2]InterdisciplinaryNanoscienceCenter,iNANO,AarhusUniversity,Denmark

AmylinisanamyloidpeptidethatformsstructureswithacytotoxicactivitythatdecreasethenumberofinsulinproducingcellsinpatientswithtypeIIdiabetesmellitus.Whilethenatureofthecytotoxicstructuresisunknown;matureamyloidfibrilsofhasbeenisolatedfromlivingtissueandnon-selective,membrane-perforatingporesofamylinhasbeenobservedinexperiments.Manyresearchersseektolearnaboutthesestructurestofindawaytoslowdownthedevelopmentofthedisease.Withall-atommoleculardynamicssimulationscombinedwiththeHighlyMobileMembraneMimiticModel(HMMM)withenhancedsamplingofmembranedynamics,wehaveinvestigatedthemembraneinteractionandself-assemblyofthispeptide.Thefocusisontheinitialself-assemblyofamylinpeptidesandhowlipidmembranescatalyzethetransformationfrommonomerstooligomers.Wehaveobservedtheshiftfromalpha-helicalmonomerstostablebeta-sheetcontainingassemblies.Withthiswehaveidentifiedregionsofthepeptidethatareimportantfortheinter-peptiderecognitionandforconnectingthepeptidesinbeta-sheets.Theseresultsfitswellwithpreviousexperimentalfindingandcanbeusedtoexplainexperimentalresultsinatom-detailedmodels,anditcaninspirefutureexperimentalandmodellingstudiesofthepeptide.

ISQBPPresident’smeeting2016–19-22June

Topic:Protein-lipidinteractions

P39:Structuraleffectoftheinterfacialtensiononphospholipidsbilayerswollenbyneutrallipids

AmélieBâcle*[1],CathyJackson[1],StefanoVanni[2]andPatrickFuchs[1]

[1]MembraneDynamicsandIntracellularTrafficking,InstitutJacquesMonod,CNRSUMR7592,UniversitéParisDiderot,15rueHélèneBrion,75013Paris

[2]Dynamicsoflipidmembranesandproteincoats,InstitutdePharmacologieMoléculaireetCellulaire,CNRSUMR7275,SophiaAntipolis,660Routedeslucioles,06560Valbonne

Lipiddroplets(LD)areintracellularorganellesthathaveacentralroleinlipidmetabolismandimplicationindiseasessuchasobesityanddiabetes.LDshaveauniquearchitecture:aphospholipidmonolayerthatsurroundsaneutrallipidcorecomposedoftriacylglycerols(TAG)andcholesterylesters(CE)[1].SomeproteinsarerecruitedbothtoLDsandtoothercellularorganelles[2],whereasothersaretargetedspecificallytothesurfaceofLDs[3].Ithasbeenshownthatsomeoftheseproteinscouldbesensitivetoahighsurfacetension(ST),increaseintheareaperlipid,inreconstitutedLD[1].HowdosurfacepropertiesdifferbetweenamembraneandLD?HowdoestheLDsurfacerespondtoanincreaseST?Weperformedall-atommoleculardynamicssimulationsontrilayersystemsthatmimictheLDsurfacetoinvestigatethesurfacepropertiesofthisorganelle.Thetrilayerwascomposedofahydrated1-palmitoyl-2-oleoylphosphatidylcholine(POPC)bilayerswollenwithtrioleins(TO)betweenthetwoleaflets.SeveralsimulationswereperformedatdifferentSTbyincreasingtheareaperPOPC.Surfacepropertieswerecharacterizedintermsofpackingdefects(i.einterfacialvoidsatthemembrane-waterinterface).NodifferencewasobservedwithaPOPCbilayeratequilibrium.However,highSTpromotedtheinsertionofTOintothePOPCmonolayerandasignificantincreaseofpackingdefects.AthoroughanalysisofTOconformationsshowedtheirtrendtoexposetheirglycerolattheinterface(“trident”conformations).Takentogether,ourresultsprovideaquantitativemolecularunderstandingofhowSTinfluencestheLDsurface.OurworkconstitutesafirststeptowardscharacterizingthebehaviorandstructureofLDsurfacepropertiesandwillbeusefulforabetterunderstandingonhowsomespecificproteinsaretargetedtoLD.

[1]Thiametal.2013

[2]Bouvetetal.2013

[3]Bulankinaetal.2009

ISQBPPresident’smeeting2016–19-22June

Table of Contents

ISQBPPresident’smeeting2016–19-22June

Talks

T1 Prof.ModestoOrozco TheBarcelonaInstituteofScienceandTechnology

T2 Prof.BernardMontgomeryPettitt UniversityofTexasMedicalBranch

T3 Mr.MahdiBagherpoorHelabad FreeUniversityofBerlin

T4 LennartNilsson KarolinskaInstitutet

T5 Dr.VladCojocaru MaxPlanckInstituteforMolecularBiomedicine

T6 Prof.ThomasE.Cheatham UniversityofUtah

T7 Dr.JoannaTrylska UniversityofWarsaw

T8 Dr.FilipLankas InstituteofOrganicChemistryandBiochemistry

T9 Dr.CarmenDomene King'sCollegeLondon

T10 Dr.SymaKhalid UniversityofSouthampton

T11 Dr.StefanoVanni CNRS

T12 MichaelSchauperl UniversityofInnsbruck

T13 Prof.RebeccaC.Wade HeidelbergInstituteforTheoreticalStudiesandHeidelbergUniversity

ISQBPPresident’smeeting2016–19-22June

T14 Prof.MartaFilizola IcahnSchoolofMedicineatMountSinai

T15 Prof.WiliamL.Jorgensen YaleUniversity

T16 Dr.DanielCappel Schrödinger

T17 Dr.ElsaSanchez-Garcia Max-Planck-InstitutfürKohlenforschung

T18 Prof.CarmayLim InstituteofBiomedicalSciences,AcademiaSinica

T19 M.Sc.SanjaZivanovic IRBBarcelona

T20 Dr.ChandraVerma A*Star,Singapore

T21 Prof.AlexanderD.Mackerell UniversityofMaryland

T22 Prof.CharlesL.Brooks UniversityofMichigan

T23 Dr.HimaBinduKolli UniversityofOslo

T24 Mr.IainABethune UniversityofEdinburgh

T25 Dr.ThomasGaillard EcolePolytechnique

T26 Dr.KwanghoNam UmeåUniversity

T27 Prof.XabierLopez EuskalHerrikoUnibertsitatea

T28 Prof.AnnickDejaegere EcoleSuperieuredeBiotechnologiedeStrasbourg

ISQBPPresident’smeeting2016–19-22June

T29 Prof.CarolB.Post PurdueUniversity

T30 Dr.NatachaGillet KarlsruheInstituteofTechnology

T31 Mr.ThibaultTubiana I2BC/CNRS

Posters

P1 Dr.PatriciaSaenz-Mendez UniversityofGothenburg

P2 MajdaMisiniIgnjatovic LundUniversity

P3 Dr.HerveMinoux sanofi

P4 Mr.NicholasMichelarakis UniversityofOxford

P5 Ph.D.AliciaMerlino FacultaddeCiencias

P6 Dr.MariaLauraLavaggi UniversidaddelaRepublica

P7 MathewRKoebel St.LouisCollegeofPharmacy

P8 Mrs.BiancaCelidetPerezDeLucani AarhusUniversity

P9 Dr.AbirGanguly Max-Planck-InstitutfuerKohlenforschung,Muelheim

P10 Mr.IainABethune UniversityofEdinburgh

ISQBPPresident’smeeting2016–19-22June

P11 Dr.SandhyaP.Tiwari RikenAdvancedInstituteforComputationalScience,Kobe,Japan

P12 Dr.PandianSokkar Max-Planck-InstitutfürKohlenforschung

P13 Dr.LarsSkjærven UniversityofBergen

P14 Prof.AlexanderD.Mackerell UniversityofMaryland

P15 JérômeEberhardt IGBMC

P16 Dr.AnnaReymer UniversityofGothenburg

P17 Mr.YossaDwiHartono KarolinskaInstitutet

P18 Dr.VladCojocaru MaxPlanckInstituteforMolecularBiomedicine

P19 CarolineSenac UPMCCNRSINSERM

P20 Mr.RaphaelPeltzer UniversityofOslo

P21 Mr.XujunLiang CEASACLAY

P22 Dr.NathalieBasdevant UniversityofEvry,France

P23 Mr.ThibaultTubiana I2BC/CNRS

P24 Dr.SofiaVasilakaki NationalandKapodistrianUniversityofAthens

P25 Dr.SandhyaP.Tiwari RikenInstitute,Kobe,Japan

ISQBPPresident’smeeting2016–19-22June

P26 Dr.SophieSacquin-Mora LaboratoiredeBiochimieThéorique,CNRSUPR9080

P27 Mr.NicolasPanel ÉcolePolytechnique

P28 KlausRomanLiedl UniversityofInnsbruck

P29 Mr.StefanMilanovIvanov A*STAR,Singapore

P30 SigbjørnLølandBore UniversityofOslo

P31 Dr.OleJuulAndersen UniversityofOxford(AcademicVisitor)

P32 Ms.TaliaZeppelin AarhusUniversity

P33 Dr.QaiserWaheed UniversityofBergen

P34 Dr.TomVenken UniversityofBergen

P35 M.Sc.SumitMittal Max-Planck-InstitutfürKohlenforschung

P36 Dr.EdvinFuglebakk UniversityofBergen

P37 Dr.PatrickF.J.Fuchs UniversitéParisDiderot,CNRS

P38 Mr.MikkelChristensen AarhusUniversity

P39 Mrs.BacleAmelie InstitutJacquesMonod-CNRS

ISQBPPresident’smeeting2016–19-22June