binding free energy: what did you learn?
TRANSCRIPT
-
Bindingfreeenergy:Whatdidyoulearn?
Florentina TofoleanuNationalInstitutesofHealth
NationalHeart,Lung,andBloodInstitute
D3RWorkshop, LaJolla,March11th 2016
-
Freeenergycalculationprocedure
Weiteratedthebinding freeenergycalculationstep:- 3timesforCBClip systems- 3-12timesforOAH/OAMe systems
-
=0
+ ++ =0
Gilson,M.K.,Given,J.A,Bush,B.L.&McCammon,J.A.Biophys.J.72,10471069(1997)Boresch,S.etal.,J.Phys.Chem.B.95359551(2003)
TheDouble-DecouplingMethod(DDM)
Gbind = GrestonC + Gelec
C + GvdWC + Grestoff
C
GvdWM Gelec
M
-
IonicconcentrationNa3PO4 ionicconcentrationsusedexperimentally: 20mM @pH7.4forCBClip 10mM @pH11.5forG1-G5inOAH/OAMe G1-G5 50mM @pH11.5forG6inOAH/OAMe
Byusing theionicstrength,wetranslatedthemintoNaCl solutions: 50mM NaCl 25mM NaCl 165mMNaCl
-
TI+Docking*
*Submission withthelowestRMS
Under-estimatingenergies
Over-estimatingenergies
CBClip calculationsperformed byDr.Juyong Lee,NIH/NHLBI.
-
BAR+Docking
-
TI+MD
-
BAR+MD
G3:consistentlyover-estimating thebinding energy
-
What went right: G1
Predicted binding pose
Binding affinity (kcal/mol)
Experiment -5.84
Calculation (TI + DOCK) -7.61 (0.75)
-
What went right: G9
Predicted binding pose
Binding affinity (kcal/mol)
Experiment -7.40
Calculation (TI + DOCK) -7.85 (0.90)
-
What went wrong: G3
Predicted binding pose
Binding affinity (kcal/mol)
Experiment -4.02
Calculation (TI + DOCK) -9.78 (2.36)
-
What went wrong: G8
Predicted binding pose
Binding affinity (kcal/mol)
Experiment -6.18
Calculation (TI + DOCK) -2.71 (0.87)
-
G2
Docking result Gas phase simulation result
-
G4
Docking result Gas phase simulation result
-
G5
Docking result Gas phase simulation result
-
G6
Docking result Gas phase simulation result
CBClip hasanopenconformation.
-
G10
Docking result Gas phase simulation result
CBClip hasasemi-openconformation.
-
RMSerrorsofallCBClip submissionsSubmission # Method Name
1 CHARMM/CGENFF/BAR/TI/TIP3P/GALAXY-DOCK/DOCKING
2 SOMD/AM1BCC-GAFF-TIP3P/MBAR/A
3 CHARMM/CGENFF/TI/TIP3P/GALAXY-DOCK/DOCKING
4 CHARMM/CGENFF/BAR/TIP3P/GALAXY-DOCK/DOCKING
5 SOMD/AM1BCC-GAFF-TIP3P/MBAR/D
6 SOMD/AM1BCC-GAFF-TIP3P/MBAR/B
7 CHARMM/CGENFF/TI/TIP3P
8 CHARMM/CGENFF/BAR/TIP3P
9 MT-1 binding free energy
10 HSA/BEDAM/OPLS2005/AGBNP2
11 SOMD/AM1BCC-GAFF-TIP3P/MBAR/C
12 MT-2 binding free energy
CBClip calculationsperformed byDr.Juyong Lee,NIH/NHLBI.
-
CorrelationsforCBClip submissionsSubmission # Method Name
1 CHARMM/CGENFF/BAR/TI/TIP3P/GALAXY-DOCK/DOCKING
2 SOMD/AM1BCC-GAFF-TIP3P/MBAR/A
3 CHARMM/CGENFF/TI/TIP3P/GALAXY-DOCK/DOCKING
4 CHARMM/CGENFF/BAR/TIP3P/GALAXY-DOCK/DOCKING
5 SOMD/AM1BCC-GAFF-TIP3P/MBAR/D
6 SOMD/AM1BCC-GAFF-TIP3P/MBAR/B
7 CHARMM/CGENFF/TI/TIP3P
8 CHARMM/CGENFF/BAR/TIP3P
9 MT-1 binding free energy
10 HSA/BEDAM/OPLS2005/AGBNP2
11 SOMD/AM1BCC-GAFF-TIP3P/MBAR/C
12 MT-2 binding free energy
-
OAH&OAMe Bindingenergies
-
OAH/OAMe andguests
Host:charge-8Guests:charged&neutral
Ions:neutralized&ionicconcentration~Na3PO4
Parameters:ParamChem CGENFF
Explicitsolvent
Drycavity(nowatermoleculeswithin)
3-12calculationsforeachsystem
K.Vanommeslaeghe,E.Hatcher,C.Acharya,S.Kundu,S.Zhong,J.Shim,E.Darian,O.Guvench,P.Lopes, I.Vorobyov,A.D.MacKerell Jr.,, J.Comput.Chem. 2010, 31,671-690
-
Ligand
Protein
GalaxyDock:Protein-LigandDockingProgram
Goal:predictthebindingposeofagivenligandwhenitisboundtoagivenprotein
Sampling
Importantforbinding Cluestoimproving
affinity
Twomaincomponents
Scoring
W. -H. Shin, J. K. Kim, D. S. Kim, C. Seok, J. Comput. Chem. 2013, 34, 2647
-
GalaxyDock-HG:Host-GuestDocking
Selectthreebinding posesforeachsystem->simulatethelowest
-
NeutralG3&G5
2.9620*
Tetramethyl-ammonium-hydroxide
DistancefromQMcalculations;courtesyofFrankPickard
-
Assessingtheguestprotonationstateinthecomplex
+ +
00
+
+
#$%&$%'(
#$%&$%')
'*+,-./012+3
fromDDMcalculations
(fromQMpKa calculations)
fromDDMcalculations
G1,G2,G4,G6=negativelychargedG3,G5=neutral
-
BindingfreeenergysubmissionsforOAH
Binding freeenergieswereunder-estimated.
NoNMRdataforG4.
Bestsubmission:TI,RMSvalues=1.36/1.46kcal/mol
-
Differencebetweenexperimentalandeachcomputedvalue.
Binding freeenergieswereunder-estimated.HighesterrorsforG4.
ErrorsforBindingfreeenergyforOAH
Bestsubmission:TI,RMSvalues=1.36/1.46
-
BindingfreeenergysubmissionsforOAMe
NoITCdataforG4andG5.ExceptforG5,energieswereover-estimated.
Bestsubmission:BAR,RMS=0.87,1.94kcal/mol
-
Differencebetweenexperimentalandeachcomputedvalue.
Binding freeenergieswereover-estimated.HighesterrorsforG4.
ErrorsforBindingfreeenergyforOAMe
Bestsubmission:BAR,RMS=0.87,1.94kcal/mol
-
ExperimentalvsComputationalDataUnder-estimatingenergies
Over-estimatingenergies
Bindingenergiesweremostlyunder-estimated.
G6 G4
G5
G6
G5
G4hadconsistentlyhigherrorswithrespecttoexperiment.WesuspectthateithertheBrionneedsre-parametrization,orthesystemisneutral(unlikely).
-
Comparisonwithothers:OAH
-
Comparisonwithothers:OAMe
-
IncavityvsAtopthecavity
G=-10.541kcal/mol G=-6.4kcal/mol
OAH
-
WhydidwegettheworstresultsforG4?
Initialparametrization QMcalculation Lonepair addition*
TI:-7.84->-4.30(kcal/mol)BAR:-4.89->-3.84(kcal/mol)OAH
OAMe TI:-9.95->-0.08(kcal/mol)BAR:-10.54->1.55(kcal/mol)
Experimentalvalue:-9.38kcal/mol
Experimentalvalue:-2.38kcal/mol
*ParametersfromAlexMacKerells group
Analyzingonlythechargedspecies
-
Brisinsidethecavity->Gismorepositive
-4.30kcal/mol -3.97kcal/mol
-2.64kcal/mol-3.84kcal/mol
TI
BAR
OAH,G4+lonepair
-
Brisinsidethecavity->Gismorepositive
-0.08kcal/mol +2.10kcal/mol
+1.96kcal/mol+1.55kcal/mol
TI
BAR
OAMeG4+lonepair
-
Take-homemessages
CBClip:lowesterrorsforsmall/rigidguests
Parametrization dictated the open/closestateofCBClip
Ionicconcentrationisimportant
Treatmentofhalogens isimportant
Furtheranalysisofhydration
-
Acknowledgements Juyong LeeNIH/NHLBI FrankPickardNIH/NHLBI GerhardKnig NIH/NHLBI
JingHuang UniversityofMaryland Chaok Seok SeoulNationalUniversity
TimMiller NIH/NHLBI RichardVenableNIH/NHLBI
BernardBrooks