tcbg highlights 2013

8/12/2019 TCBG Highlights 2013

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Highlights 2013

Theoretical andComputational

Biophysics GroupUniversity of Illinois at Urbana-Champaign

NIH Center for MacromolecularModeling & Bioinformatics

www.ks.uiuc.edu


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Motivated by biomedically relevant problems and collabo-rating closely with experimental laboratories, the Theoretical and Computational Biophysics Group (TCBG), NIH

Center for Macromolecular Modeling and Bioinformatics, exploits

advances in physical theory and computing to model living organ-isms across many levels of organization, from molecules to cells tonetworks. Over the years, the group has pioneered the modeling ofvery large biomolecular structures, as well as the combination ofquantum mechanical and classical mechanical simulations. High-lights of our groups research and software tool development arepresented each month on our website and are represented here.

Director: Professor Klaus Schulten(Physics)

Professor Laxmikant Kal (Computer Science)Professor Zaida Luthey-Schulten(Chemistry)

Professor Emad Tajkhorshid (Biochemistry)

Professor Alek Aksimentiev (Physics)

Research by the TCBG is funded by the National Institutes of

Health (NIH 9P41GM104601), the National Science Foundation,

and the University of Illinois.

2 | TCBG Highlights 2013


3/17

Cryptic Light Receptor

January 2013

Animals and plants, together with other life forms, possess inter-nal clocks that attune them to the daily rhythm on Earth. A sign ofsuch clocks is jet lag, the discomfort experienced by humans when

due to travel across several time zones our internal clocks need tobe reset to the new time zone. Feed-back to local day light assiststhe resetting and a key light receptor serving the purpose is aprotein called cryptochrome. The name was chosen as the receptorhid for a long time from the instruments of researchers, but todaythe name seems still appropriate as the physical mechanism of the

receptor is shrouded in mystery andsubject to dispute. Adding to themystery is an apparent second roleof cryptochrome, namely that of asensor for the Earth magnetic field,

which helps migratory birds andmany other animals in long-rangenavigation. The biological functionof cryptochrome supposedly arisesfrom a photoactivation reactioninvolving electron transfer, butthe reaction pathway is difficult toresolve experimentally as the bestavailable method, time-resolvedspectroscopy, cannot identifyunequivocally the photoproducts

produced through cryptochromelight absorption. Experimentalists hate to admit the calamity, butlikely the only way out are a combination of quantum-chemicaland classical molecular dynamics calculations. Such calculationswere recently performed and the results reported. The calculationsdemonstrate that after absorption an electron is transferred insidecryptochrome, the new state becomes stabilized through protontransfer and decays back to the proteins resting state on timescales allowing the protein, in principle, to act as a light as well asmagnetic sensor.

I A. S, T D, A R. M. S,and K S. Decrypting cryptochrome: Revealing the

molecular identity of the photoactivation reaction.Journal of

the American Chemical Society,134:18046-18052, 2012. (PMC:

3500783)



4/17

Everybody Can Fold Proteins

January 2013

Every living cell relies on proteins to carry out its functional tasks;every protein needs to assume a proper shape in order to be opera-tional for these tasks. How a protein, composed of a particular

sequence of amino acids, could find its way to a proper shape is afundamental, yet mysterious biological process. Researchers havesought to unravel atomistic details of protein folding processesthrough computer simulations, but modeling such processes

is computationally demanding. It was onlyrecently that some researchers have been ableto observe in some case how proteins fold, butneeded for the purpose the fastest comput-ers available today. One of these computers isAnton, the expensive special-purpose super-computer available essentially only to a single

research group. Is there an affordable way tosimulate protein folding? One solution could becoarse-grained methods. These methods savetremendous computational effort by replacingcomputational models that include all atomisticdetail. However, the simplified models need

to include a sufficiently accuratedescription of proteins for model-ing folding processes. As reportedrecently, researchers have overcomethe challenge by combining atomis-

tic and coarse-grained descriptions.The new method is fast enough tofollow movements of proteins longenough to see them fold, whilerequiring only readily available com-

puter powers. The new method allowed researchers to analyze com-plete folding events for seven proteins, including a protein, called3D, that is one of the largest proteins ever folded computationally.

W H and K S. Further optimization of a

hybrid united-atom and coarse-grained force field for folding

simulations: Improved backbone hydration and interactionsbetween charged side chains. Journal of Chemical Theory and

Computation,8:4413-4424, 2012. (PMC: 3507460)



5/17

How Membranes Curve

February 2013

The cells of higher life forms, so-called eukaryotic cells, are subdi-vided through many internal membranes made of lipid bilayers.The internal membranes assume numerous shapes, like spheres,

tubes or parallel sheets. Outside of cells, biological membranesadopt usually flat shapes and the question arises, how do eukary-otic cells sculpt their inner membranes? The question of flatmembrane sculpting is particularly interesting also as mature cellsconstantly produce new membrane shapes, for example sphericalvesicles filled with certain biomolecules destined for release intothe extracellular space, a process called exocytosis. The cell hasmany mechanisms available for sculpting its membranes, one ofthem relying on proteins called BAR domains that act from the

surface of lipid bilayers. Molecularmodeling with NAMD and VMD

has provided valuable views ofBAR domains at work in case of theso-called N-BAR family. Research-ers report now an extension of theearlier studies to the F-BAR domainfamily of membrane sculptingproteins. The new modeling workis particularly exciting as it canbe directly compared to electronmicroscopy images of membranetubes sculpted from flat membranes

in experiments done outside ofcells. The new studies reveal howF-BAR domains sculpt tubularmembranes through the shape ofdimerized domains and throughF-BAR domains not acting indi-vidually, but as an army of F-BARdomains adopting an orderedformation on one side of themembrane.

H Y and K S.Membrane sculpting by F-BAR

domains studied by molecular

dynamics simulations.PLoS

Computational Biology,

9:e1002892, 2013. (PMC: 3561051)



6/17

Hot Quantum Effects

February 2013

Quantum mechanics rules all natural processes, but is manifestedmost strongly when acting on the lightest particles, namely thewell-known electrons. To study quantum effects physicists rou-

tinely resort to very low temperature, that of liquid helium. Amaz-ingly, living systems seem to exploit quantum effects for theirbenefit, but do so at temperatures typical for life, namely aroundroom temperature or warmer. A particularly important case isphotosynthetic light harvesting where so-called quantum coher-

ence plays a critical role when electrons in assem-blies of chlorophylls become excited by sun lightand the excitation energy is harvested by utilizingit to charge photosynthetic membranes. In order tounderstand how photosynthesis can exploit roomtemperature quantum effects one needs to know

how the temperatures, which are much higherthan those in the physics laboratories where liquidhelium is employed for cooling, affect electronbehavior. The knowledge can be gained by so-calleddissipative quantum mechanical descriptions, butthe needed computer calculations are extremelydemanding. To address this demand, research-ers have developed the software PHI that uses thepower of parallel computers, as described in a recentreport. PHI has already been used to understandhow many chlorophyll molecules act together to

absorb sunlight among themselves and let theexcitation migrate between chlorophylls to so-calledreaction centers where the excitation energy is con-verted into a membrane potential. The overall lightharvesting process has been described in variousreports and in a review. The PHI software can beobtained from our web site.

J S and K S. Open quantum

dynamics calculations with the hierarchy equations of motion

on parallel computers.Journal of Chemical Theory and

Computation,8:2808-2816, 2012. (PMC: 3480185)J S, M S, and K S. How

quantum coherence assists photosynthetic light harvesting.

Journal of Physical Chemistry Letters,3:536-542, 2012. (PMC:

3404497)

J S and K S. Excited state

dynamics in photosynthetic reaction center and light

harvesting complex 1.Journal of Chemical Physics, 137:065101,

2012. (8 pages). (PMC: 3427344)6 | TCBG Highlights 2013


7/17

Molecular Tortoise

March 2013

For newly made membrane proteins, getting to their final destina-tion in the membrane requires another protein, the channel SecY,to provide a pathway. But just knowing the route is not enough,

because SecY presents the nascent protein with a choice: insertinto the membrane or cross the channel to the watery exterior. Howthe nascent protein comes to a decision has long been a point of

uncertainty, althoughit has been presumedto be driven by purelyenergetic consider-ations, i.e., the proteingoes to the environ-ment it ultimatelyprefers. Now, recent

simulations and free-energy calculationsspanning time scalesfrom nanoseconds allthe way to secondshave revealed thathow long the nascent

protein deliberates in the channel is just as great a factor in itsfinal location as how favorable it is there. It was found that thelonger the protein takes to decide, the more likely it is to choose themembrane, proving that, at least for membrane insertion, slow and

steady wins out.

J C. G, I T, B R, and K

S. Reconciling the roles of kinetic and thermodynamic

factors in membrane-protein insertion. Journal of the American

Chemical Society, 135:2291-2297, 2013. (PMC: 3573731)

J F, J G, E O. S,

S F, M G, B B,

T M, O B, T B,

K S, and R B. Cryo-EM structure

of the ribosome-SecYE complex in the membrane environment.

Nature Structural & Molecular Biology,18:614-621, 2011. (PMC:3412285)

J G, C C, and K S.

Free energy of nascent-chain folding in the translocon. Journal

of the American Chemical Society, 133:7602-7607, 2011. (PMC:

3100187)



8/17

Good News for the Easter Bunny

April 2013

Rabbit hemorrhagic disease is extremely contagious and associ-ated with liver necrosis, hemorrhaging, and high mortality in adultrabbits. First described in China in 1984, within a few years, rabbit

hemorrhagic disease spread to large parts of the world and todaythreatens the rabbit industry and related ecology. The disease iscaused by a virus, aptly named rabbit hemorrhagic disease virus.As reported recently, a group of experimental and computationalresearchers combining crystallography, electron microscopy anddata-guided molecular dynamics simulations utilizing NAMD

determined an atomicmodel of the capsid,namely the proteinshell that surrounds thegenetic material of the

virus. The capsid simu-lations involved 10million atoms and havebecome feasible onlythrough Blue Waters,a brand new petascalesupercomputer. Theatomic model, analyzedby means of VMD,recently adapted tostudies of very large

structures, resolves thestructural frameworkthat furnishes bothmechanical protectionto the viral genes aswell as a quick releasemechanism after a

virus enters a host cell. Researchers can use the detailed knowledgeof the capsid structure to develop vaccines against rabbit hemor-rhagic disease.

X W, F X, J L, B G, YL, Y Z, J M, K Z, T S. B,

K S, D Z, H P, and F S. Atomic

model of rabbit hemorrhagic disease virus by cryo-electron

microscopy and crystallography.PLoS Pathogens,9:e1003132,

2013. (14 pages). (PMC: 3547835)



9/17

Eyes of Plants

May 2013

The ability to sense light is crucial for both plants and animals;animals use their vision to navigate and interact with their sur-roundings, whereas plants grow toward light to optimize photo-

synthesis. One of the most important photosensors in plants relieson tiny molecular switches known as LOV domains. When lightstrikes a LOV domain, it causes the formation of a single chemicalbond; the unique structure of the LOV domain converts this subtle

change into a protein unfolding event thattriggers signaling. The mechanism throughwhich LOV domains amplify bond formationinto large-scale molecular motion is of greatinterest both for designing light-activatedproteins for synthetic biology applications,and as a model for understanding the harder-

to-study molecular switches that govern mostof the functions of living cells. As reportedrecently, researchers used a series of long-timescale molecular dynamics simulationsto show the locations of molecular levers thatallow light-induced bond formation to rear-range the entire structure of the LOV domain.The simulations highlighted two main pathsof information flow from the heart of the pho-toreceptor to the surface of the protein, givingunprecedented insight into the function of this

light-activated molecular switch.

P L. F, K H. G,

and K S. Signaling

mechanisms of LOV domains: new

insights from molecular dynamics studies.

Photochemical & Photobiological Sciences,

12:1158-1170, 2013. (PMC: 3679247)

S-H S, P F,

A N, E C, K

S, K G, and D S.

L. Modulating LOV domain photodynamics with a residuealteration outside the chromophore binding site.Biochemistry,

50:2411-2423, 2011. (PMC: 3068209)

P L. F, M D, and K S.

Dynamic switching mechanisms in LOV1 and LOV2 domains

of plant phototropins.Biophysical Journal,91:3630-3639, 2006.

(PMC: 1630464)



10/17

Elusive HIV-1 Capsid

June 2013

Human immunodeficiency virus type 1 (HIV-1) is the major causeof AIDS, for which treatments need to be developed continu-ously as the virus becomes quickly resistant to new drugs. When

the virus infects a human cell it releases into the cell its capsid,a closed, stable container protecting the viral genetic material.

However, interaction with the celltriggers at some point an instabilityof the capsid, leading to a well-timedrelease of the genetic material thatmerges then with the cells genesand begins to control the cell. Thedual role of the capsid, to be func-tionally both stable and unstable,makes it in principle an ideal target

for antiviral drugs and, in fact,treatments of other viral infectionssuccessfully target the respectivecapsids. The size of the HIV-1 capsid(about 1,300 proteins), and its irregu-lar shape had prevented so far theresolution of a full capsid atomic-level structure. However, in a tour deforce effort, groups of experimentaland computational scientists havenow resolved the capsids chemical

structure (deposited to the proteindata bank under the accessioncodes 3J3Q and 3J3Y). As reportedrecently, the researchers combinedNMR structure analysis, electronmicroscopy and data-guided molec-ular dynamics simulations utilizing

VMD to prepare and analyze simulations performed using NAMDon one of the most powerful computers worldwide, Blue Waters, toobtain and characterize the HIV-1 capsid. The discovery can guidenow the design of novel drugs for enhanced antiviral therapy.

G Z, J R. P, E L. Y, X

M, B C, J N, J A, A M.

G, K S, C A, and

P Z. Mature HIV-1 capsid structure by cryo-electron

microscopy and all-atom molecular dynamics.Nature, 497:643-

646, 2013. (PMC: 3729984)



11/17

Finding the End

July 2013

DNA, a long linear molecule, is the carrier of genetic information.In the cell, each DNA molecule is packaged in a structure calledchromosome. The ends of linear chromosomes are capped by

structures known as telomeres to prevent fusion with neighbor-ing chromosomes. Telomeres are maintained by an enzyme called

telomerase during DNAreplication. In order to doso, telomerase has to findthe telomere region onDNA quickly and precisely.One telomerase is theprotelomerase TelK, whichbinds to the ends of DNA,cleaves DNA strands and

refolds cleaved DNA endsinto hairpin telomeres inlinear chromosomes of pro-karyotes and viruses. Previ-ous studies have shownthat TelK is only active asa dimer. In a recent study,researchers investigatedthe target-search mecha-nism of protelomerase TelK

through single-molecule experiments and molecular dynamics

simulation. It was revealed that as a monomer, TelK undergoesone-dimensional diffusion along non-specific DNA (without telo-mere sequence), and is able to bind to the target site preferentially.There, the target-immobilized monomer waits for a second bindingpartner to form an active protein complex.

M P. L, X Z, L W, W M H,

K S, and Y R. C. DNA target sequence

identification mechanism for dimer-active protein complexes.

Nucleic Acids Research,41:2416-2427, 2013. (PMC: 3575837)



12/17

Quantum Biology

August 2013

Clearly, the laws of physics hold and are exploited in living organ-isms. Speaking as a physicist, most biological characteristics stemfrom the laws of classical physics that students learn in their first

year. However, crucial characteristics in organisms are governedby quantum physics, a higher and still active area of physics.The latter characteristics are those in which biological processesinvolve the jumps of electrons from one state to another state:electrons are exemplary quantum particles. The quantum behav-ior of electrons cover all chemical transformations, for example incase of formation or breaking of chemical bonds, but it arises alsoin optical transitions induced through light absorption by biomol-ecules. Quantum behavior of electrons in such cases is localized insingle molecules, but it can also spread over many biomoleculesin a typical quantum mechanical fashion. The biomolecules form

in such case a chorus that sings in one coherent voice, rather thanchatters incoherently. This type of behavior is not only of interestto the modern biological researcher, but also to modern physicsresearchers working on quantum computing. Three recent reviewssummarize fascinating quantum behavior in biology as it comesabout in vision, photosynthesis, and animal navigation using theearth magnetic field. In case of vision twelve electrons in a mol-ecule called retinal correlate their motion during light absorptionand steer the optically excited molecule to alter its shape, therebyinitiating an extremely sensitive response to light. In case of pho-tosynthesis, molecules of chlorophylls utilize thermal effects to

optimally absorb sun light and then share the resulting electronicexcitations among themselves through quantum coherence. In thecase of animal navigation, quantum effects apparently bring abouta magnetic compass that can sense the Earth field through itsinteractions of biomolecules despite the fact the interaction energyamounts to only a tiny fraction of thermal energy present at bodytemperature; physicists are eager to learn the trick as it might teachthem how to build quantum computers without costly cooling toextremely low temperatures.

S H and K S. Quantum biology

of retinal. In Masoud Mohseni, Yasser Omar, Greg Engel, and

Martin B. Plenio, editors, Quantum Effects in Biology,pp. 237-263.Cambridge University Press, 2014.

I K and K S. Structure, function, and

quantum dynamics of pigment-protein complexes. In Masoud

Mohseni, Yasser Omar, Greg Engel, and Martin B. Plenio, editors,

Quantum Effects in Biology,pp. 123-143. Cambridge University

Press, 2014.

I S, T D, and K S.

Separation of photo-induced radical pair in cryptochrome to a

functionally critical distance. Scientific Reports,4:3845, 2014.

doi: 10.1038/srep03845.



13/17

May the Force Field Be With You

September 2013

Structural biologists are increasingly turning to simulationmethods to investigate the connections between molecular struc-ture and biological function. Classical molecular dynamics (MD)

simulations, such as those performed by the simulation softwareNAMD, rely on potential energy functionsrequiring parameters to describe atomicinteractions within the molecular system.While these parameters are available for themost commonly simulated biopolymers (e.g.,proteins, nucleic acids, carbohydrates), manysmall molecules and other chemical specieslack adequate descriptions. The complex-ity of developing these parameters severlyrestricts the application of MD technologies

across many fields, including most notablydrug discovery. Recently, researchers havedeveloped software, the Force Field Toolkit(ffTK), that greatly reduces these limitationsby facilitating the development of parametersdirectly from first principles. ffTK, distrib-uted as a plugin for the molecular modelingsoftware VMD, addresses both theoreticaland practical aspects of parameterization byautomating tedious and error-prone steps,

performing multidimensional optimizations, and providing quan-

titative assessment of parameter performanceall from within aneasy-to-use graphical user interface.

C G. M, J S, K S, E

T, and J C. G. Rapid parameterization

of small molecules using the Force Field Toolkit. Journal of

Computational Chemistry,34:2757-2770, 2013. doi: 10.1002/

jcc.23422. (PMC: 3874408)



14/17

Avoiding the Gridlock

October 2013

Traffic flow in a city is affected by large-scale features, like thelayout of road networks, as much as it is by small-scale ones, liketraffic lights at a road junction. Likewise, the transport of small

molecules in cells occur on multiple scales. For example, ions dif-fusing through the mechanosensitive channel of small conductance(MscS) must navigate the intricate geometry of the MscS, whichvaries by the ngstrom. At the same time, the distribution of ionswithin hundreds of ngstroms of the MscS fluctuate as ions escapethrough the channel, thus changing the electrostatic landscapeseen by other ions as they approach the MscS. In order to modelboth the fine and bulk aspects of diffusion in systems like that ofthe MscS, scientists have proposed, in a recent report, a methodthat marries the high spatial resolution of molecular dynamics

to long range diffusion. In the new description, bio-

molecules diffuse by hopping through a grid underthe influence of Coulomb and other forces.

I T and K S. A computational

kinetic model of diffusion for molecular systems.

Journal of Chemical Physics,139:121929, 2013. (PMC:

3795746)

R G, M S, C

C, and K S. Cytoplasmic domain

filter function in the mechanosensitive channel of

small conductance.Biophysical Journal, 101:80-89,

2011. (PMC: 3127185)

V V, M S, J

C-M, K S, and E

P. A structural mechanism for MscS gating

in lipid bilayers. Science, 321:1210-1214, 2008. (PMC:

2897165)

V V, M S, D. M C,

B R, K S, and E P. Three

dimensional architecture of membrane-embedded MscS in the

closed conformation. Journal of Molecular Biology,378:55-70,

2008. (PMC: 2703500)

M S, V V, E P, and

K S. Ion conduction through MscS as determined

by electrophysiology and simulation.Biophysical Journal,

92:886-902, 2007. (PMC: 1779981)

M S and K S. Molecular dynamics

study of gating in the mechanosensitive channel of small

conductance MscS.Biophysical Journal,87:3050-3065, 2004.

(PMC: 1304777)14 | TCBG Highlights 2013


15/17

Roadmap for Protein Folding

November 2013

Every protein in a living cell needs to assume a proper structurein order to fulfill its biological function. The proteins that fails todo so cause malfunction of cells, often leading to disastrous dis-

eases. Thus, how a protein folds into its native structure is oneof the central biological processes that need to beunderstood. The modern view of protein folding sug-gests that a folding process is governed by structuraltransitions among a wide spectrum of structures thata protein could access; all of these possible struc-tures and associated transitions constitute a complexroadmap for protein to follow, very much like the onecommonly used to navigate a car to its destinationthrough the best route. Obtaining comprehensive andaccurate roadmaps for protein folding are essential

for the characterization of correct folding routes. Intheory, such a roadmap could be explored throughcomputational simulations using an accurate modelincluding every atomistic detail; in practice, the struc-tural complexity of proteins turns the exploration ofits roadmap into a daunting computational task. Asreported recently, researchers have demonstrated anefficient way to explore roadmaps for protein folding

by utilizing a hybrid model which combines atomic models for theprotein part with a fast simplified model for the surrounding waterpart in order to achieve both accuracy and efficiency. By investigat-

ing folding mechanisms of two proteins, the researchers showedthat their approach is able to generate folding roadmaps as accu-rate as those obtained with complete atomic models while onlytaking days to finish the task, much faster than the complete atomicmodels that usually need months.

W H and K S. Characterization of folding

mechanisms of Trp-cage and WW-domain by network analysis

of simulations with a hybrid-resolution model. Journal of

Physical Chemistry B,117:13367-13377, 2013. doi: 10.1021/

jp404331d. (PMC: 3811923)



16/17

Physics Meets DNA

December 2013

Characterizing the genetic makeup of individuals can help selectthe best treatment for individuals, but requires that sequencingof the whole DNA of patients can be achieved for less than $1000.

Fortunately, recent discoveries in physics promise help. Indeed, thediscovery of the thinnest material known to mankind, graphene,promises a new and cheaper way to sequence human DNA. Asreported in a prior study, graphene pores can conduct electro-phoretically DNA through very small pores, so-called nanopores.A new study has demonstrated that graphene, forming a singleatomic layer thin stripe with a nanopore in the middle, can conductan electrical current, the sheet current, around the pore. The sheet

current is sensitive to the DNA passing through thepore and may even sense the passing DNAs sequence.In this case monitoring the current can establish a

DNA sequence reader. The sensitivity of the sheetcurrent depends critically on an orderly passage ofDNA. Optimal sensitivity can arise when the passingDNA is stretched mechanically. Molecular dynam-ics simulations using NAMD suggest conditions formechanically manipulating DNA for optimal sequenceanalysis.

A G, C S, K

S, and J-P L. Graphene

quantum point contact transistor for DNA

sensing.Proceedings of the National Academy of

Sciences, USA,110:16748-16753, 2013. doi: 10.1073/

pnas.1308885110. (PMC: 3801026)



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Theoretical and ComputationalBiophysics Group

www.ks.uiuc.edu

NIH Center for MacromolecularModeling & Bioinformatics

tcbg highlights 2013

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