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John D. Chodera url http://www.choderalab.org email [email protected] github https://github.com/choderalab ORCIDiD 0000-0003-0542-119X twitter @jchodera mobile 415.867.7384 post 1275YorkAve,Box357 NewYork,NY10065 Educationandpositions 2013– AssistantProfessor,Physiology,Biophysics,andSystemsBiologyProgram, WeillCornellGraduateSchoolofMedicalSciences 2012– AssistantMember,MemorialSloan-KetteringCancerCenter 2008–2012 IndependentDistinguishedPostdoctoralFellow,CaliforniaInstituteforQuantitativeBiosciences(QB3), UniversityofCalifornia,Berkeley Independentresearchfunding,sponsorsPhillipL.GeisslerandSusanMarqusee 2006–2008 Postdoctoralresearcher,DepartmentofChemistry,StanfordUniversity WithVijayS.Pande(headofFolding@Homedistributedcomputingproject) 1999–2006 PH.D.inBiophysics,UniversityofCalifornia,SanFrancisco Committee:KenA.Dill,MatthewP.Jacobson,VijayS.Pande 1995–1999 B.S.inBiology,CaliforniaInstituteofTechnology UndergraduateresearchwithPaulH.Patterson(experimentalmolecularneurobiology) andJerryE.Solomon(computationalchemistry) Fellowshipsandawards 2017 SiliconTherapeuticsOpenScienceFellowship 2013–2016 LouisV.GerstnerYoungInvestigatorAward 2013–2014 GoogleExacycleforExternalFaculty 2008–2012 QB3-BerkeleyDistinguishedPostdoctoralFellowship,UniversityofCalifornia,Berkeley 2005–2006 IBMPredoctoralFellowship 2005 FrankM.GoyanAwardforoutstandingworkinphysicalchemistry,UniversityofCalifornia,SanFrancisco 2000–2005 HowardHughesMedicalInstitutePredoctoralFellowship Researchoverview Myresearchfocusesonredesigningthewaywedevelopsmallmoleculesforchemicalbiologyanddrugdis- coveryandbringingrigorousatomisticmodelingintothehigh-throughputbiologyandgenomicsera. By combiningnovelalgorithmicadvancestoachieveorders-of-magnitudeefficiencygainswithpowerfulbutin- expensiveGPUhardwareanddistributedcomputingtechnologies,Iamdevelopinganewgenerationoftools andopensourcesoftwarepackagesforpredictingsmallmoleculebindingaffinities,designingsmallmolecules withdesiredproperties,quantifyingdrugsensitivityorresistanceofclinicalmutations,andunderstanding thedetailedstructuralmechanismsunderlyingoncogenicmutations.AsacorememberoftheFolding@home Consortium,mylabharnessesthecomputingpowerofhundredsofthousandsofvolunteersaroundtheworld tostudyfunctionalimplicationsofmutationsandnewopportunitiesfortherapeuticdesignagainstcancer targets.Usingautomatedbiophysicalmeasurements,wecollectnewexperimentaldatatargetedtoadvancethe quantitativeaccuracyofourmethodologies,andgathernewinsightintodrugsusceptibilityandresistancein kinasesandothercancertargets.MyworkmakesextensiveuseofscalableBayesianstatisticalinferencemeth- odsandinformationtheoreticprinciplesfordesigningexperimentsandquantifyingerror.Iampassionateabout openscience,disseminatingsoftwareengineeringbestpractices,andmaximizingresearchreproducibility. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-1 Publications GoogleScholarstatistics:http://goo.gl/qO0JW MyNCBIBibliography:http://goo.gl/e3kjgK h-index:36/i10-index:52/citations:6906(18Feb2018) ∗asteriskdenotesequalcontributions annualcitationcounts(GoogleScholar)–18Feb2018 SubmittedandUnderReview Abl:TKI Co-Crystal Structures Underreview bioRχiv · HauserK,NegronC,AlbaneseSK,RayS,SteinbrecherT,AbelR,ChoderaJD,andWangL AccuratelypredictingtargetedkinaseinhibitorresistancetoclinicalAblmutationsusing alchemicalfree-energycalculations Weshowhowalchemicalfreeenergycalculationscanbeusedtopredictwhetherclinicalpointmutationsinhumankinasedomains conferresistanceorsusceptibilitytotargetedkinaseinhibitors. Abl:axitinib Abl:bosutinib Abl:dasatinib Abl:imatinib Abl:nilotinib Abl:ponatinib PDB: 4WA9 UnPdDerBr: e3vUieEw4 PDB: 4XEY PDB: 1OPJ PDB: 3CS9 PDB: 3OXZ (A) (B) · P1 DFrG-ouit stma2tes1 e34 8 AsWApHU6rg7715 sa2 inhnsgaoantScmoMmT∗ayr75b,5k GiTynre75e9a sotriaoghnkiooiufncGha∗es,meMoipglleernrooWmmTi,icRsse,cssuttrJouScu,tCsuhrfaooldberiroailnoJDghy,i,FabannidEtdSomePreosli+l?geecruMlarAsimulationapproaches,weidentifyasetofhumankinasesthat 2983765 areespeciaAspl7l29y promiscuousbindersofsmallmoleculekinaseinhibitors,andshowthataprototypicalmemberofthisclass,DDR1,achieves DFG-in states thispromiscuitybyvirtueofitsmorestableAsp-DFG-outconformation. (C) DFG-out DFG-out (D) WT D671N WDFTG-out DFG-inDDF6G7-1oNut DFG-in YY775559AA Underreview (kcMaUl/mEo l) 1.24 11..2251 0.79 00..8709 VersYi75o5AnFebrDFuG-inarYy759A16,201DFG8-insubmitt0e dRtou5f0m Eofl npfhotEs1rp00ho aFpte ty,ranM1s5f0e rreud / sre2c0e 0 tt2a50 JM· ,ThompsonA,LakeE,CyphersS,Albanese5oSfK27,HansonSM,BehrJM,ThomasDT,ChoderaJD,andLevinsonNM AdynamicmechanisRmMfSoEr allosteri1c.a9c1tivation1o.f12AurorakinaseAbyactivationloop 1.87 1.11 phosphorylation (kcal/mol) 1.87 1.11 ThroughacombinationofFRET,IR,andEPRlabelingandlarge-scalemoleculardynamicssimulations,weshowthatphorphorylation activatesAurorakinasebyanovelmechanismthatdoesnotsimplycorrespondtoaDFG-outtoDFG-inshift. Prime Inrevision bioRχiv FEP+ · PartonDL,HansonSM,Rodríguez-LaureanoL,AlbaneseSK,GradiaS,JeansC,SeeligerM,ChoderaJD ExpeArnimoepnetnlibraryofhumankinasedomainconstructsforautomateEdxbpaecrtiemrieanltexpression WeengineeralibraryofhumaRnekisniassteadnotm oarinnsowti tchlaussesfiufilcbaatcitoenrialexpressionusinganovelphosphatasecoexpressiontechnique. 131 S N R 131 S N R 0.698 0.902 Accuracy 0.695 0.899 n s 0 5 1 0.690 0.901 n s 1 9 2 o 0.727 0.940 o dicti n 1 U7n6der8review bioRSχpivecificity 0.726 0.719 0.938 0.938 dicti n 0 96 4 Pre r 0 F3a1ssJ,Si9vakDA,C·rooksGSE,eBneasuitcihvaimtypKA,0L.e5im0k 00u.h.55le10rB,and0C.6ho7d 00e.r.6a68J6D Pre r 0 7 12 Quantifyingconfiguration-samplingerrorinLangvevinsimulationsofcomplexmolecularsystems Weaddressa0fu.n6d5amentalquestionregardingwhymoleculardynamicssimulationworksdespitethefactthat0t.h8e4useoffinitetimesteps Accuracy: 0.65 Susceptibleor Neutralor Resistant Accuracy: 0.83 leadstoerror i0nt.h6e4sampledprobabilitydensitiesandpopulations,demonstratinghowtomeasureconfiguratio n0-.s8pa3cesamplingerrorfor animportantclassofLangevinintegratorswidelyusedinbiomolecularsimulation. Figure2. Differentnumericalintegratorsintroducedifferenterrorstructureinphasespace, illustratedinadouble-welUlsnysdteemr.Hreerve,iewweillusbtriaoteRthχetiimvestep-dependentdiscretizationerror introducedbyfourintegratorsona1Ddouble-w·ellpotential[U(x) x6+2cos(5(x+1))]. RossGA,RustenburgAS,Grinaway⌘PB,FassJ,andChoderaJD Thetoprowof2Dcontourplotsillustratesthedifferencebetweenthephase-spacedensityr(x,v) Biomolecularsimulationsunderrealisticsaltconditions sampledatthemaximumtimestepconsidered(Dt=0.7,closetothestabilitylimit)andtheequilibrium densityp(x,v);solidlinesWindeicsahteopwoshitoivwecNonCtoMurCs,cwahnilebdeaushseeddlitnoesimindpilceamteennegtaatinveecfofinctioeunrst.osmostatinmoleculardynamicssimulationstomodelrealisticfluctuationsin Thebottomrowof1Ddensiiotynpelontvsisrhoonwmsteimnetssteapr-odeupnedndbeniotmpeortluercbuatlieons,inanthdesilalmupstlerdatmearhgoinwalthelocalsaltenvironmentaroundbiologicalmacromoleculescandiffer distributioninconfigurationspace,rx,withtheequilibriumdistributionpxisdepictedasasolidblack line.Thesampledmarginasludbisstrtiabunttioianlslyrxfarroemshbowunlkf.orincreasinglylargetimesteps,denotedrDt, depictedbyincreasinglylightdottedlines,forDt=0.3,0.6,...,0.7(arbitraryunits).Inspectingthe contourplotssuggeststhatsomeintegratorsplittings(especiallyVRORV)induceerrorthatfortuitously “cancelsout”whenthedensityismarginalizedbyintegratingoverv,whiletheerrorinotherintegrator splittings(ORVRO,OVRVO)constructivelysumstoamplifytheerrorinconfigurationspace. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-2 Inrevision bioRχiv · WojnarowiczP,DesaiB,ChinY,LimaeSilvaR,OhnakaM,LeeSB,CaoMG,OuerfelliO,XuS,GoldgurY,MillerM,ChaudharyJ,GarlandW, StollerG,AlbaneseSA,SoniR,PhilipJ,HealeyJ,VinagoluR,NortonL,RosenN,HendricksonR,IavaroneA,DannenbergA,ChoderaJD, PavletichN,LasorellaA,CampochiaroP,BenezraR Asmall-moleculepanIdantagonist,AGX51,showsstronganti-tumorandanti-neovascular activity Weidentifythebindingmodeofanewsmall-moleculepan-Idantagonistpriortoitsconfirmationbymassspectrometrycrosslinkingdata. Underreview chemRxiv · GillS,LimNM,GrinawayP,RustenburgAS,FassJ,RossG,ChoderaJD,andMobleyDL BindingModesofLigandsUsingEnhancedSampling(BLUES):RapidDecorrelationofLigand BindingModesUsingNonequilibriumCandidateMonteCarlo NonequilibriumcandidateMonteCarlocanbeusedtoacceleratethesamplingofligandbindingmodesbyordersofmagnitudeover instantaneousMonteCarlo. Underreview · IntlekoferAM,ShihAH,WangB,NazirA,RustenburgAS,AlbaneseSK,PatelM,FamulareC,CorreaFM,ArcilaME,TaylorJ,TallmanMS,Roshal M,PetskoGA,ChoderaJD,ThompsonCB,LevineRL,Stein,EM AcquiredclinicalresistancetoIDHinhibitionthroughintransIDH2mutations ClinicaldoublemutationsactingintransincancerpatientsreceivingIDH2inhibitorsactthroughanovelbiophysicalmechanism. PUBLISHEDANDINPRESS NatureMaterials,inpress DOI · Kdye Kdye KdrSuhgamayY,ShahJK,TdsrcuhgaharganehDF,RoxburyD,Budhathoki-UpretyJ,IȷsikM,MizrachiA,NawalyK,SugarmanJL,BautE,NeimanMR, pure/aq aq/np aq/np pure/aq JohnsonDC,SridharanR,ChuKL,RajasekharVK,ChoderaJD,LoweSW,andHellerDA Quantitativeself-assemblypredictionyieldstargetednanoparticles Adecisiontreebasedonpredictedphysicalpropertiesandandmoleculardescriptorsiscapableofpredictingtheassemblyofdrug/dye nanoparticlesthatcanbeusedintumor-targetedselectivekinaseinhibitortherapytominimizeon-andoff-pathwaytoxicity. Dye in Drug in Pure dye solvent Nanoparticle solvent Pure drug NatureChemicalBiology13:402,2017 DOI a L194 b0.4 CyWWp12h ++TTeppxx22r ((s(cid:111)(cid:111)==11S74..83, nnRss))uffcE,B40ehrJM,Chodde2350r0000aJ3D0 nM, enazymne cdonceLntreatiovni·nsonNM eKinase activity (RFU/min)1102257055050000002 nWpMhT oeWsnzpQy3hm1oe8r 5ycMoMlantcWQDeedn1 1Kt 8rS(aW51tiLio6Tmn)2uflaNormalized activityWKinase activity (RFU/min)Qt00112345i2...1E050o0000000000801n058Q1u- n11(cid:43)p8Mh5+oM es1np0zhQy[o-Tmr1py8C (t)xela+25 QQCQt]cL(ey(cid:43)11o120ds88M8n0 -55.5(lcQ)iC20MLCtee- y1N ns80t+-5-rl+TaiTAACIdArkOaNtetppTNi3)oxnpx0en2x2l2 t i5evltalc0oWWnelcleget12oKinase activity (RFU/min)hisv r--o1uakdTT1234wt0app0000y0oxx5e0000r22ns0000Tn0i rf((iedp0m(cid:111)(cid:111)fi1e==eci5es95WcH0 ..er(Cr492mnTc ep nsnn3AhaMoA),ss2xtoh ))a0esrimnco0p,zQcghyev1ttmoWr8rec2ei5ym ei5ocMvleoa1a0tonta5ecsanaexdnidnn e(tntQrcW-+Correlaion time (ns)baTcT1tagciiTpo8pax)123onoe5xw2o000L205B es lrnl0nixe,WBhncmadWbL1Kinase activity (RFU/min)WTieishyteeou1112(n025p257eWtoQ050505aTaln0000000rH1zat1oif38aprW0lyQ5nbl zny,agL21xM-)8m SpW oQ5e-+ygcy2hTmCnT11ozhpNpl3y8xgsWexmei4.2mp52ae1 xsh2M r scoehomesrCnyKinase activity (RFU/min)3cylleaegsadnHt-112letpi3r050:5tadade000cx0st 4i000(0io,0Cntutr1105yaC050Cues9a000n-y-eo000lspi00att-thesl4io)t+treedesipomm,hdoduQ2r-syo1uel8auc5t0n+ehhMldara t(y1Cpyt-yidQ-sFir7-o1ldoi8rito+e5so)LnTnrn·ipgxn2todD eaogangilnyfOtaeaessLnIeioC-mn,2abRpnF-ulodoehslntmpdyeriddnanoblgtranou@otnreehgxatdoAtywemiSogh,neoylSudrsaretrltkaavoahetggeareSolnae,Gafavtfsueseeeuncrtnrtuspnehn.rrdsirsMeoianrRgulg,ollgCoyshhsshotitaadfetbelsrrlteiaienchJrsDyuand,bcCarsotrttgoirievasvnstaeeJbtRuosi,tonuaildnnibzdnasiTetntihtorwoAnamottruphkesraouotunnhrsdCaaeeBvrelbiehysigh JournalofChemical&EngineeringData62:1559,2017 DOI · MatosGDRandKyuDYandLoefflerHHandChoderaJDandShirtsMRandMobleyDL Approachesforcalculatingsolvationfreeenergiesandenthalpiesdemonstratedwithanupdateof theFreeSolvdatabase WereviewalchemicalapproachestocomputingsolvationfreeenergiesandupdateFreeSolv—themostpopulardatabaseofhydrationfree energiesofneutralmolecules—withmorecomputedandexperimentalproperties. Spine Spine PLoSComputationalBiologyHM13:e1005659T,px22017 DOI EastmanP,SwailsJ,ChodeC-rhealixJD,McGibQ1b85onRC-Thel,ixZhaoY,Beauc·hampKA,WangLP,SimmonettAC,HarriganMP,BrooksBR,andPandeVS OpenMM7:RapiddeveloWatpermentofhighperformancealgorithmsformoleculardynamics Water network network ThelatestversionoftheGPU-acceleratAeudrAmolecpuT28l8arsimulationOpenMMfeaturesavarietyofincrediblyflexiblebutfasttoolsforrapidly PKA prototyping,evaluating,anddeployingnewsimulationalgorithms. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-3 PLoSComputationalBiology12:e1004728,2016 DOI · PartonDL,GrinawayPB,HansonSM,BeauchampKA,andChoderaJD Ensembler:Enablinghigh-throughputmolecularsimulationsatthesuperfamilyscale Wedemonstrateanewtoolthatenables—forthefirsttime—massivelyparallelmolecularsimulationstudiesofbiomoleculardynamicsat thesuperfamilyscale,illustratingitsapplicationtoproteintyrosinekinases,animportantclassofdrugtargetsincancer. JournalofClinicalInvestigation126:3529,2016 DOI · XuJ,PhamCG,AlbaneseSK,DongY,OyamaT,LeeCH,Rodrik-OutmezguineV,YaoZ,HanS,ChenD,PartonDL,ChoderaJD,RosenN, ChengEH,andHsiehJJ Mechanisticallydistinctcancer-associatedmTORactivationclusterspredictsensitivityto rapamycin WeusemassivelyparalleldistributedmolecularsimulationsonFolding@hometoprobethemechanismactivatingmutationsofthemTOR kinaseidentifiedinclinicalpopulations. bioRxiv preprint first posted online June 29, 2015; doi: http://dx.doi.org/10.1101/021659; The copyright holder for this preprint is the author/funder. It is made available under a CC-BY 4.0 International license. ￿ ￿￿￿￿￿￿￿￿￿￿￿A￿￿￿JWfC￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿oitrtdNnf9ouo￿onoooih￿0fnsoemerrirO￿nmttl↵e⌧�nyee(itu%cosnvAd—ghmurˆ￿eftegme￿oe[El0aw0t%irnpdrnq￿rii,saf(fopToi￿bt.aelwxeorelmt]l￿n%clraeees?ea￿froRtecddvrcedrrathMc,ae-Frksha�eotscaleilS0a)Arhcghlsnalˆeiy(rwitpuonifesz)ceaelicerutaeoidraalvetroirltmseJhasezwdiouownioan￿ltsantlrpienDtncdth.agfiagcehoesoueftHoomyr—tinndesismnhonh(icdttatlne￿wt(raChtypatreatii.hameedomao￿obrwtdvvreen￿heseueeaegd￿siahoroldsmmlr￿lyrivl)arfneo￿.ietdeoplateeuhr±eleWgmefolbsreefeisrwr￿eieoohmxoretss.eemrfniie￿rltttloxnei￿tedrh￿pnodhprac.ad￿￿eftieietths�nhs￿ie￿id￿nchlsnAiiegˆ￿.s￿ttcoaf￿geeity[)rcag￿matdtr￿odot0i￿raiolen0￿s,mdi±teT￿fnodasgaeteaq￿t]sio￿gkdm±a￿cerudc.ynoem)nh￿lp￿loi￿.uelgo%dip￿imae.mcbiw￿aedo￿txvTprp￿crriln￿ieaneedfmfoa￿￿dotrgdnrdi,￿rrriehoesgzoooafmet￿ridneeo0rrt---,oearloucarthiyuotonat.noaudmtCoamotmaetpidcuaetllaqytduioeitnleibr1m2ria:n1tin7iog9tn9he,d2eeq0tu1eil6icbt·raiDotenOdirInegimonoolfeacmuolalercuslaimrsiumlualtaitoionn,salongstandingchallenge ￿￿￿ DISCUSSION ￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿Fvlaop((artcbaijbiposc￿sthemwtadwttsmeearhuoiihoeionerfy￿￿liovaeaIomfcmcnhiaovisenineulrtGaalinnsBn￿mreveztsnegesztlhesnstonbidelsituridtitc-irityvcb.rurleinrnatintetvrracaai?eohbaantolzeeaeahtesyilnadgtagggnitxses3bilfabgmpiasivTd’rienrdwnesttoioda-s.ubEcbutkipdlemlf,ivfaagentfuhioodekfeercitvnm=otilociaarcaanrohayrntrsieiatenodiaoiorbhdsoz￿soicrtnhmteBssspgrvtf2aterieoiwamieoindmmeituamaeiaiseaiaaiwc0aat.csaqraecNtsnvcstslhatns0aneeatiahafpserviitinhuidtcUiulsaeato0oltnowqtnn-toceiridhloaogiithvanineetsd⌧enl↵etdvnlnugtvicieaghihilalitsmnocdsve0acanklabetgiitffeftfpetreydetoteeolouhrrloiogrnrvielrii(hurs,ioerqiodonsis￿ebraaa0taaefovroqaneec￿i(iminumttnbnriretnsfismhaaewd(idus⌧￿hehinatiifotrcbcFaoiemeaoiloiu0￿sae)atrerirttecemineuflqnirtsiourcerfbinaiatgltiaooredahmotoeulurciissrophttlecreuaslu0t,endr￿leaeietnilrra(fkliytygaqmml⇠ytpplagiirriianoi(i.rtaaxcnmifoesecebustfilt-lldoiomdonueearoimuaitxtaednroiodirHc9emenandlieitrlspf￿rairllnaiaeoptuivpe0osgot(sbotgvteaeeioaetn1eytinintlniainsenc￿rae⌧iwtcpntdioss0qsi8sguvdaihc,ohg,leiotmtctt)eutntluomu0laabsta0r.s￿uoefpiheeieotomwirric0imoatntruoatImmie)lauwemeroeeuuitfriaciiarlteoiaenlambrp⌧delsofsslsilatrlusapsmyennelcd)bhrnrflilt)aof⌧itoteelijyna.ibenipyi)ngtecveadeteaicelxi)ms,blvmthanigchaaeatsrcetAeeersseeleizctceoa0yicoeainlettrseacsa￿0oad.Eeotomliaeoicrwrspntyndzbteagrnttirqmiit)nsorebibalcc?iseeritsanrc[heostyizsiotwetmdhhcme￿iitimpqse,ecae0tarsnoamebsi￿Waonodaeeeeae,xudotttsp.opnsTaitbpdnifhacsi,rrewnimbiecnhmtofsseancu]eeln,dedelaToee0,ieoeteep.enbsoeyltbtatiar0cnrlqFadtsndlathgDendsawealtrxyrrog,hislieetdtutv0rkmddnjaiagiionekfwmhteeieonesmaled,armiurtttrnnesfcldvweaogeiogroiliasswo[rpirotipjosactolaabettteezneomthvtso￿￿￿￿￿￿￿￿u￿ctra￿ehwfgwti0cin￿t￿￿￿￿￿￿￿e￿rvtrr￿seorbte￿￿￿￿￿￿￿￿￿et￿ri￿thdaeaccea,iauiasmhgnfthegileearartia1aqoitosbaewuetTett0anmmslthethnNadgyb0msfauti.ntenlscd0t.aiotisgerntemieepeoi�teneo]ihercoiognBcecpgo[evaaot——Bonrorrcfadnsr4iin￿iinh↵uleenehleyg0eeeeyssstssssr.￿t--tf---eft,windt,aho,h￿diliancDiot￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿u￿￿￿￿￿￿T￿￿￿￿￿￿a￿sRdJMwpJBMTlt￿￿￿￿￿￿h￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿s￿￿￿￿￿￿￿￿￿￿ig]pni￿￿￿m￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿e￿￿￿.oniioictlseuegentmtatibrtpbepotaoatfgcnepuvgseoootpsnHoc￿teiihhhinueoarcvaeooessllbapfso?iiiemoototoilotaAparaslriqrreeettasrinTAAeayrsrtioozsttIanniicrnilliisnsslincyeiuhcfselilitopemmqluuaoncoehlisaesrtos.omawisi,lghtlctaeerstbPioiortdraohsitrtuutbpetsomitywritramemS,eleaaflualsyerteos7nslnnecmeateim0lilsutemtaohcentgirstdkietlttytesspotirrrfrdhlehsmu,iisooseetehmtogiliogenddcaaeirobesiooagleaotraseoontplilddegtuilefhsivrcpsnasanvidr.ePmennoiheqpofcpcanipeadflcntatantscaeiatgnretacda4ebahccysatxdlufilesapwoiiecotiotaerlxmmrhoheebfuo[lruesucatiatiolccidxatiluipsotnederdrnlidnmyhrolnairtitulslaamemampt0ynpeeeaiittieaa-eurfsi,sctpbroucvbonnn,ecoasurch,o,uohawacttlep—rreiturheaioborhltctbcmarnrlTicicdusrsttwsectcyoimuOahnaaidaennoelyalludlfewelifierlhiataieedtrrAhony]mwtnmsttttfiruiyasbyrgpreonee—nilariioscadsneehieifdPnenrieoozeeegnffnnoortd,trettcacuenoeeloodtvraSlsewh.ieIifdeloerrsrtnheaaignsdronerorooosst.lfnclfeiiIsItwesuatt￿iunpaalgomerAiMetwruhvpfMfmsibvsncoofsstucbtavlntfebnstnAttileeaiaspmiileffasiehioheirebcwhUmngileinlwinsMiormserrabwfyaiorsplcdcreeteoilsrowdhsiytnutdgLmipacdicteeohfbhieinistrtrintheac.chuKreohue￿iaArtolosrvgeetgnnheSiveCPdaeeeohkrarnhAoenneasaetTtwsc.ltsrlianaswiidfceprnbe￿sndcsbi—eaEsisedplecrnotsIneiepmrfioreosmyitronGlttOetlro,—odreetiiqatAeds[waetrrohgnewiymehczbraleettrpu￿nwlthmssumraNltauro.easecaihwchtn￿ae.pwjeeeee—rDdoeutaiydcehbueptglfco.]F￿ngaitrriseuresuoDraa.aoeeshresehe￿oecd,hstsrulsse(pixbnstornvhsslOsodytnpEiegaraseumtpadtiuiiaauuwoauprlcoieumilmotaoaoecaTyaotcBevtocadmnvcciesltarootna￿oaaoxlwueamrtvgAssirhhap￿kianenpede----fanlulaotsyntiraaapaobIriatphgcosseintcisldLtplglchnemilselslyoylrnuaahttieeeerioelcSlseiapodrteaitccsiiha.nyossbtsetrtmoeebiamipsonc,nahwceiocbhtceiacwthltotnHannialhffarest:cahnmarmlcfcpencreond,tneumitsctginhoyleeodlhtasahseerrtth.xirdairecsktwaioorhhofEmnatntiqdpvieonetIo—oittdblnimenionqtelrociaeuaeitnyfcettsrtmaeaceeesioho.Jzvirpetwirdtn￿cltGtlsiastndoqqlaiouhe￿s—meeiraiieehcmoeeilasieJa￿blzntauuedcceeMrtsyhhntmelhrdfitinl,gfp.CHjireiiaeetenlmebeseeemell,eaia,soiurciipvwnruihsuoogshncnrmxebbnenttmttanattpemtrctmibtLp￿atwchcirrltaviseiolmoitnehw,fhmaahn,￿eiyilwwiithr.r—htdnAarsstgo.ottieeaaciiedayhotyegohetuRtaiiieebiuirtmcnntoooaalanehixncsnaorrrmaegalcetiioliddnnnnngeeeeeeessatt------)flmyieudsxdmBsfidsmaie,fteebciOerdsnlvaudneotrelnebMsrtlnmmiwoyuat-cpoyroiwrBngehdlctaeeAehac1hmcnDlrSati9ueein,,lteawlBl9MigeacTrran:atpor1ykhegdlbrlDc2eyotileihoenteC9asyroncsgstI1mciD,oiqrpogK2moLuialnorb,,etfrpo,a2oMtsueun3ao0nimtdtn0tfelL1ieCeort:poi9-ha5hndrmgnseeo4uKau·ddSi5i,rcDdtieAseac,aoernttMc2Oaidideynac0JPrcCgfIDruL1lfifhofcg5ro6ohcehddeerei·exixecevseeDariennarnegceOfinJetirDs-,sgewebI.i.fleuadosttesotrrhf:tdetNhribsaeteenrnsiaSbcfetuhArtmlibMioaqenrtuPkwcioinLedeeg5fnfidaccnaeiqdhenuniamestlsoilptuferoisoner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SivakDA,ChoderaJD,andCrooksGE Timesteprescalingrecoverscontinuous-timedynamicalpropertiesfordiscrete-timeLangevin integrationofnonequilibriumsystems Wederiveasimple,easy-to-implementLangevinintegratorthathasuniversallyusefulpropertiesinmolecularsimulations. PhysicalReviewX4:011020,2014 DOI · PrinzJ-H,ChoderaJD,andNoéF Spectralratetheoryfortwo-statekinetics Wepresentanewmathematicalframeworkforunifyingvarioustwo-stateratetheoriespresentedinthephysicalchemistryliterature overmanydecades,andprovideaquantitativewaytomeasurereactioncoordinatequality. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-4 JournalofComputerAidedMolecularDesign27:989–1007,2013 DOI · WangK,ChoderaJD,YangY,andShirtsMR IdentifyingligandbindingsitesandposesusingGPU-acceleratedHamiltonianreplicaexchange moleculardynamics Weshowhowboundligandposescanbeidentifiedevenwhenthelocationofthebindingsitesareunknownusingthemachineryof alchemicalmodernfreeenergycalculationsongraphicsprocessors. JournalofPhysicalChemistryB117:9956–9972,2013 DOI · WangL-P,Head-GordonTL,PonderJW,RenP,ChoderaJD,EastmanPK,MartinezTJ,andPandeVS Systematicimprovementofaclassicalmolecularmodelofwater Wateristhemostimportantmoleculeinbiology,andaccuratetreatmentofitsinteractionsiscriticaltoaccuratemodelingfordrug discovery.Whilepolarizablemodelsofwatercanachieveveryhighaccuracies,theyarebothdifficulttoparameterizeandexpensiveto employ.Here,weshowhowahighqualityinexpensivepolarizablemodelofliquidwatercanbederivedusinganautomated parameterizationengine. PhysicalReviewX3:011007,2013 DOI · SivakDA,ChoderaJD,andCrooksGE Usingnonequilibriumfluctuationtheoremstounderstandandcorrecterrorsinequilibriumand nonequilibriumdiscreteLangevindynamicssimulations Allmoleculardynamicssimulationsintroduceerrorintothesampleddistributionbyvirtueofthefinitetimestepusedtointegratethe equationsofmotiononadigitalcomputer.Whiletraditionalapproachestoanalyzingthiserrorareextremelycomplicated,weshowhow interpretingfinite-timestepintegratorsasaformofnonequilibriumdrivingleadstosimple,straightforwardschemesforassessingthe impactoftheseerrors,aswellascorrectingforthem. JournalofChemicalTheoryandComputation9:461,2012 DOI · EastmanP,FriedrichsMS,ChoderaJD,RadmerRJ,BrunsCM,KuJP,BeauchampKA,LaneTJ,WangL,ShuklaD,TyeT,HoustonM,StichT,Klein C,ShirtsMR,andPandeVS OpenMM4:Areusable,extensible,hardwareindependentlibraryforhighperformancemolecular simulation InexpensiveconsumerGPUspromisea100-foldincreaseinsimulationpowerbyproblemsthatcaneffectivelyexploittheirhighly specializedstructure.Here,wedescribethelatestadvancesinanextremelyhighperformance,open-source,extensibleGPU-accelerated libraryandtoolkitformolecularsimulation. BiophysicalJournal103:1490,2012 DOI · ElmsPJ,ChoderaJD,BustamanteCJ,MarquseeS Thelimitationsofconstant-force-feedbackexperiments Popularconstant-force-feedbacksingle-moleculeexperimentscancausesevereartifactsinsingle-moleculeforcespectroscopydata.We demonstrateasimplealternativethateliminatestheseartifacts. ProceedingsoftheNationalAcademyofSciences109:3796,2012 DOI · ElmsPJ,ChoderaJD,BustamanteC,MarquseeS Themoltenglobulestateisunusuallydeformableundermechanicalforce Wemeasurethephysicalpropertiesofthemoltenglobulestateofapo-myoglobin,andshowthatitisunusuallydeformablecomparedto typicalproteinnativestates. JournalofChemicalTheoryandComputation8:3445,2012 DOI · PiteraJWandChoderaJD Ontheuseofexperimentalobservationstobiassimulatedensembles Weshowhowtheconceptofmaximumentropycanbeusedtorecoverunbiasedconformationaldistributionsfromexperimentaldata, andhowthisconceptrelatestothepopular‘ensemblerefinement’schemesforNMRdataanalysis. Science334:1723,2011 DOI · KaiserCM,GoldmanDH,ChoderaJD,TinocoI,Jr.,andBustamanteC Theribosomemodulatesnascentproteinfolding Usingsingle-moleculeforcespectroscopy,weshowhowtheribosomeitselfmodulatesthefoldingdynamicsofnascentproteinchains emergingfromtheexittunnel. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-5 PhysicalReviewLetters107:098102,2011 DOI · ChoderaJDandPandeVS Splittingprobabilitiesasatestofreactioncoordinatechoiceinsingle-moleculeexperiments Wedemonstrateasimpletestforidentifyingpoorreactioncoordinatesinsingle-moleculeexperiments. AnalyticalBiochemistry414:297,2011 DOI · TellinghuisenJTandChoderaJD Systematicerrorsinisothermaltitrationcalorimetry:Concentrationsandbaselines Awordofcautionaboutlargeerrorsinisothermaltitrationcalorimetrymeasurementsarisingfromligandconcentrationerrors. JournalofChemicalPhysics134:024111,2011 DOI · MinhDDL,ChoderaJD Estimatingequilibriumensembleaveragesusingmultipletimeslicesfromdrivennonequilibrium processes:Theoryandapplicationtofreeenergies,moments,andthermodynamiclengthin single-moleculepullingexperiments Wederiveanewestimatorforestimatingequilibriumexpectationsfromnonequilibriumexperiments,andshowhowitcanbeusedto estimateavarietyofusefulquantitiesinsimulatedsingle-moleculeforcespectroscopyexperiments. ProceedingsoftheNationalAcademyofSciences108:E1009,2011 DOI · NilmeierJP,CrooksGE,MinhDDL,andChoderaJD NonequilibriumcandidateMonteCarloisanefficienttoolforequilibriumsimulation WepresentasignificantgeneralizationofMonteCarlomethodsthatprovideanenormouslyusefultoolforenhancingtheefficiencyof molecularsimulationsandenablingmoleculardesign. JournalofChemicalPhysics134:244108,2011 DOI · PrinzJ-H,ChoderaJD,PandeVS,SmithJC,andNoéF Optimaluseofdatainparalleltemperingsimulationsfortheconstructionofdiscrete-state Markovmodelsofbiomoleculardynamics Wedemonstratehowmultitemperaturedatafromparalleltemperingsimulationscanbeusedtoconstructfullytemperature-dependent modelsofthedynamicsofbiomolecularsystems. JournalofChemicalPhysics134:244107,2011 DOI · ChoderaJD,SwopeWC,NoéF,PrinzJ-H,ShirtsMR,andPandeVS Dynamicalreweighting:Improvedestimatesfordynamicalpropertiesfromsimulationsat multipletemperatures Wedescribehowreweighingtechniquescanprovideoptimalestimatesoftemperature-dependentdynamicalpropertiesfromsimulations conductedatmultipletemperatures. ProceedingsoftheNationalAcademyofSciences108:4822,2011 DOI · NoéF,DooseS,DaidoneI,LöllmannM,SauerM,ChoderaJD,andSmithJC Dynamicalfingerprints:Atheoreticalframeworkforunderstandingbiomolecularprocessesby combinationofsimulationandkineticexperiments Wepresentanewframeworkforcomparingessentialfeaturesofthedynamicsbetweenexperimentandsimulationtoidentifythekinetics processescontributingtoindividualrelaxationtimescalesinperturbation-responseorcorrelationspectroscopyexperiments. JournalofChemicalPhysics135:194110,2011 DOI · ChoderaJDandShirtsMR ReplicaexchangeandexpandedensemblesimulationsasGibbssampling: Simpleimprovementsforenhancedmixing Weshowhowasimplechangetothewayexchangesarehandledinthepopularreplica-exchangesimulationmethodologycan astronomicallyincreaseefficiencyatnoincreaseincomputationalcost. JournalofPhysicalChemistryB114:2549,2010 DOI · PonderJW,WuC,RenP,PandeVS,ChoderaJD,MobleyDL,SchniedersMJ,HaqueI,LambrechtDS,DiStasioRAJr.,Head-GordonM,Clark GNI,JohnsonME,andHead-GordonT CurrentstatusoftheAMOEBApolarizableforcefield TheAMOEBApolarizableforcefieldisabletoreproduceadiversesetofphysicalchemicalphenomenontohighaccuracy. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-6 JournalofChemicalPhysics133:105102,2010 DOI · ChoderaJDandNoéF ProbabilitydistributionsofmolecularobservablescomputedfromMarkovmodels. II.Uncertaintiesinobservablesandtheirtime-evolution AsimpleBayesianapproachforthemodelingofstatisticaluncertaintiesinkineticandequilibriumquantitiescomputedfromMarkov statemodelsofbiomoleculardynamics. BiophysicalJournal98:3062,2010 DOI · AdelmanJL,ChoderaJD,KuoIW,MillerTF,andBarskyD ThemechanicalpropertiesofPCNA:ImplicationsfortheloadingandfunctionofaDNAsliding clamp MolecularsimulationsofthePCNAclampresponsibleforDNApolymeraseprocessivityshowasurprisinglysmallenergeticpenaltyforthe deformationrequiredforclamploading.Featuredonissuecover. JournalofChemicalPhysics131:045106,2009 DOI · BacalladoS,ChoderaJD,andPandeVS BayesiancomparisonofMarkovmodelsofmoleculardynamicswithdetailedbalanceconstraint ABayesianschemeforcomparingstatespacedecompositionsforMarkovstatemodelsofbiomoleculardynamicsthatincorporatesthe factthatphysicalsystemsmustobeydetailedbalance.ThispaperutilizesrecentresultsfromMarkovchaintheoryonedge-reinforced randomwalks. JournalofChemicalPhysics131:134110,2009 DOI · MinhDDL,ChoderaJD Optimalestimatorsandasymptoticvariancesfornonequilibriumpath-ensembleaverages Wederiveanoptimalestimatorandcorrespondingstatisticaluncertaintiesforinferringexpectationsofbidirectionalnonequilibrium processes.Theseestimatorshavewidespreadapplicabilityinsingle-moleculebiophysicalforce-spectroscopyexperimentsand nonequilibriummolecularsimulations. JournalofChemicalPhysics129:124105,2008 DOI · ShirtsMR,ChoderaJD Statisticallyoptimalanalysisofsamplesfrommultipleequilibriumstates Wepresentahighlygeneral,statisticallyoptimalapproachforproducingestimatesoffreeenergiesandequilibriumexpectationsfrom multiplesimulationsthatprovablyextractsallusefulinformationfromthedata. JournalofMedicinalChemistry51:769,2008 DOI · NichollsA*,MobleyDL*,GuthrieJP,ChoderaJD,andPandeVS Predictingsmall-moleculesolvationfreeenergies:Ablindchallengetestforcomputational chemistry Ablindevaluationoftheaccuracyofalchemicalfreeenergymethodsforcomputinggas-to-watertransferfreeenergies(solvationfree energies)ofsmallmoleculesdemonstratesthatmodernforcefieldsarelikelysufficientlyaccuratetobeusefulindrugdesign. JournalofPhysicalChemistryB112:938,2008 DOI · MobleyDL,DillKA,andChoderaJD Treatingentropyandconformationalchangesinimplicitsolventsimulationsofsmallmolecules Anquantitativeexaminationofhowmuchconformationalentropycontributestohydrationfreeenergiesofsmallmolecules,with implicationsforligandbinding. JournalofPhysicalChemistryB111:13052,2007 DOI · ShirtsMR*,MobleyDL*,ChoderaJD,andPandeVS Accurateandefficientcorrectionsformissingdispersioninteractionsinmolecularsimulations Weidentifyamajorsourceofsystematicerrorinabsolutealchemicalfreeenergycalculationsofligandbindingandshowhowasimple procedurecaninexpensivelyandaccuratelyeliminateit. JournalofPhysicalChemB111:2242,2007 DOI · MobleyDL,DumontE,ChoderaJD,BaylyCI,CooperMD,andDillKA Comparisonofchargemodelsforfixed-chargeforcefields:Small-moleculehydrationfree energiesinexplicitsolvent Wecompareanumberofpopularmethodsforderivingchargemodelsforsmallmolecules,derivinglessonsaboutbestpracticesfor accuratesimulations. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-7 JournalofMolecularBiology371:1118,2007 DOI · MobleyDL,GravesAP,ChoderaJD,McReynoldsAC,ShoichetBK,andDillKA Predictingabsoluteligandbindingfreeenergiestoasimplemodelsite Weshowhowalchemicalfreeenergycalculationsarecapableofaccurateblindpredictionofsmall-moleculebindingaffinitiestoasimple modelproteinbindingsite. JournalofChemicalandTheoreticalComputation3:1231,2007 DOI · MobleyDL,ChoderaJD,andDillKA Confine-and-releasemethod:Obtainingcorrectbindingfreeenergiesinthepresenceofprotein conformationalchange Wepresentageneralschemeforobtainingcorrectligandbindingaffinitieswhenproteinconformationalchangeisimplicatedinligand binding. JournalofChemicalPhysics126:155101,2007 DOI · ChoderaJD*,SinghalN*,SwopeWC,PiteraJW,PandeVS,andDillKA AutomaticdiscoveryofmetastablestatesfortheconstructionofMarkovmodelsof macromolecularconformationaldynamics Proposingoneofthefirstautomatedalgorithmsfordiscoveringkineticallymetastablestatesofbiomoleculesfrommolecularsimulations, thispapershowshowmanybiomoleculescanpossessnumerousdistinctlong-livedconformationalstateseventhoughthetheequilibrium populationsofthesestatesmaytoosmallforstandardstructuralbiologytechniquestodetect. ProceedingsoftheNationalAcademyofSciences104:11987,2007 DOI · OzkanSB,WuGA,ChoderaJD,andDillKA ProteinFoldingbyZippingandAssembly Areviewoftheutilityoftheproposedzippingandassemblymechanismfortheconcomitantformationofsecondaryandtertiary structureinproteinfoldingforpredictingfoldingpathwaysandnativestructures. JournalofChemicalTheoryandComputation3:26,2007 DOI · ChoderaJD,W.C.Swope,J.W.Pitera,C.Seok,andK.A.Dill Useoftheweightedhistogramanalysismethodfortheanalysisofsimulatedandparallel temperingsimulations Theweightedhistogramanalysismethod(WHAM),amainstayofmoleculardynamicssimulationanalysis,isthoroughlyexplainedand modernizedfortheanalysisofsimulatedandparalleltemperingsimulationdata. JournalofChemicalPhysics125:084902,2006 DOI · MobleyDL,ChoderaJD,andDillKA Ontheuseoforientationalrestraintsandsymmetrycorrectionsinalchemicalfreeenergy calculations Weillustratehoworientationalrestraintscanbeusedtogreatlyreducethecomputationaleffortinalchemicalcalculationsofligand bindingfreeenergies,andclarifyhowsymmetrycorrectionsarenecessarywhenmoleculescontainsymmetricorpseudosymmetric substituents. MultiscaleModelingandSimulation5:1214,2006 DOI · ChoderaJD,SwopeWC,PiteraJW,andDillKA Long-timeproteinfoldingdynamicsfromshort-timemoleculardynamicssimulations Weshowhowthelong-timedynamicsofbiomolecularsystemscanberecapitulatedfromstatisticscollectedfromshortmolecular simulationssamplingtransitionsbetweenkineticallymetastablestates. JournalofComputationalChemistry24:89,2003 DOI · SeokC,RosenJB,ChoderaJD,DillKA MOPED:Methodforoptimizingphysicalenergyparametersusingdecoys Weproposeanewwaytooptimizeparametersforaphysicalenergyfunctionusingdecoystructuresforproteinfoldingstudies. JournaloftheAmericanChemicalSociety123:12837,2001 DOI · LeeTS∗,ChongLT∗,ChoderaJD,andKollmanPA Analternativeexplanationforthecatalyticproficiencyoforotidine5’-phosphatedecarboxylase AcombinedQMandMDanalysisofpotentialplausiblemechanismstoexplaintheenormouscatalyticaccelerationofoneofthemost proficientenzymesknown. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-8 ReviewsandCommentaries CurrentOpinioninStructuralBiology25:135,2014 DOI · ChoderaJDandNoéF Markovstatemodelsofbiomolecularconformationaldynamics AreviewofexcitingrecentdevelopmentsinthestochasticmodelingofbiomoleculardynamicsusingtechniquesIoriginallyco-developed tostudyproteinfolding. AnnualReviewsinBiophysics42:121,2013 DOI · ChoderaJDandMobleyDL Entropy-enthalpycompensation:Roleandramificationsforrationalliganddesign Entropy-enthalpycompensationislikelyauniversalphenomena,butnotassevereaswidelythought,andirrelevantfordrugdiscovery andliganddesign. CurrentOpinioninStructuralBiology21:150,2011 DOI · ChoderaJD,MobleyDL,ShirtsMR,DixonRW,BransonKM,andPandeVS Freeenergymethodsindrugdiscoveryanddesign:Progressandchallenges Areviewofcurrentopportunitiesandchallengesforalchemicalfreeenergycalculationsindrugdiscoveryanddesign. JournalofChemicalPhysics134:174105,2011 DOI · PrinzJH,WuH,SarichM,KellerB,FischbachM,HeldM,ChoderaJD,Schütte,andNoéF Markovmodelsofmolecularkinetics:Generationandvalidation CurrentbestpracticesforthegenerationandvalidationofMarkovstatemodelsfordescribingthestochasticdynamicsofbiomolecular systems. ProceedingsoftheNationalAcademyofSciences108:12969,2011 DOI · ChoderaJDandPandeVS TheSocialNetwork(ofproteinconformations) Anewmethodologyformappingproteinconformationalspacesisreminiscentofhowweusetwo-dimensionalmapstonavigatea three-dimensionalworld. AnnualReportsinComputationalChemistry3:41,2007 DOI · ShirtsMR,MobleyDL,ChoderaJD Alchemicalfreeenergycalculations:Readyforprimetime? Areviewofcurrentalchemicalfreeenergymethodologiesandtheirpotentialforuseindrugdiscoveryandliganddesign. CurrentOpinioninStructuralBiology17(3):342,2007 DOI · DillKA,OzkanSB,WeiklTR,ChoderaJD,andVoelzVA Theproteinfoldingproblem:Whenwillitbesolved? Areviewofthecurrentstateoftheproteinfoldingproblem. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-9 Preprintsaheadofsubmission Preprintaheadofsubmission bioRχiv · BoyceSE,TellinghuisenJT,andChoderaJD Avoidingaccuracy-limitingpitfallsinthestudyofprotein-ligandinteractionswithisothermal titrationcalorimetry Wedemonstratehowtoavoidaccuracy-limitingproblemsinstandardisothermalcalorimetryexperimentsaswellascapturetheprimary sourcesofuncertaintyinthermodynamicparameters. Preprintaheadofsubmission arχiv · ChoderaJD,NoéF,HinrichsNS,KellerB,ElmsPJ,KaiserCM,Ewall-WiceA,MarquseeS,andBustamanteC BayesianhiddenMarkovmodelanalysisofsingle-moleculebiophysicalexperiments WepresentaBayesianhiddenMarkovmodelanalysisschemethatallowsbiomolecularconformationaldynamics—andthe correspondinguncertaintyduetolimiteddata—tobeinferredfromsingle-moleculetrajectories.Thisapproachwasdevelopedfora single-moleculestudyexaminingfoldingdynamicsofnascentproteinsexitingtheribosome[Science334:1723,2011·DOI]. Preprintaheadofsubmission arχiv · ChoderaJD,ElmsPJ,SwopeWC,PrinzJ-H,MarquseeS,BustamanteC,NoéF,andPandeVS Arobustapproachtoestimatingratesfromtime-correlationfunctions Wepresentasimple,robustapproachtoestimatingtwo-staterateconstantsfromexperimentalorsimulationdata. ScientificAdvisoryBoards 2013– Schrödinger,LLC Peerreviewerforscientificjournals Bioinformatics,Biopolymers,ChemicalPhysics,Computation,DrugDiscoveryToday,EuropeanBiophysics Journal,Entropy,InternationalJournalofMolecularSciences,JournaloftheAmericanChemicalSociety,Journal ofChemicalTheoryandComputation,JournalofComputer-AidedMolecularDesign,JournalofComputational Chemistry,JournalofComputationalPhysics,JournalofPhysicalChemistry,JournalofPhysicalChemistry Letters,MolecularPhysics,MultiscaleModeling&Simulation,NatureChemistry,NatureCommunications, NaturePhysics,PacificSymposiuminBiocomputing,PLoSComputationalBiology,PLoSOne,Proceedingsof theNationalAcademyofSciences,ScientificReports,Structure AcademicService MSKCC HighPerformanceComputingSteeringCommittee 2012–2015 Member,Co-administratorofMSKCCGPUHPCresource GraduatePrograms 2013– PrograminPhysiology,Biophysics,andSystemsBiology(PBSB) Tri-InstitutionalPhDPrograminChemicalBiology(TPCB) 2013– Tri-InstitutionalPrograminComputationalBiologyandMedicine(CBM) 2013– GerstnerSloanKetteringGraduateProgram(GSK) 2015– JOHND.CHODERA-SLOANKETTERINGINSTITUTE-10

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We show how alchemical free energy calculations can be used to predict whether clinical point mutations in human kinase domains confer resistance Under review ·. Ruff EF, Muretta JM, Thompson A, Lake E, Cyphers S, Albanese SK, Hanson SM, Behr JM, Thomas DT, Chodera JD, and Levinson NM.
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John D. Chodera url http://www.choderalab.org email [email protected] github https://github.com/choderalab ORCIDiD 0000-0003-0542-119X twitter @jchodera mobile 415.867.7384 post 1275YorkAve,Box357 NewYork,NY10065 Educationandpositions 2013– AssistantProfessor,Physiology,Biophysics,andSystemsBiologyProgram, WeillCornellGraduateSchoolofMedicalSciences 2012– AssistantMember,MemorialSloan-KetteringCancerCenter 2008–2012 IndependentDistinguishedPostdoctoralFellow,CaliforniaInstituteforQuantitativeBiosciences(QB3), UniversityofCalifornia,Berkeley Independentresearchfunding,sponsorsPhillipL.GeisslerandSusanMarqusee 2006–2008 Postdoctoralresearcher,DepartmentofChemistry,StanfordUniversity WithVijayS.Pande(headofFolding@Homedistributedcomputingproject) 1999–2006 PH.D.inBiophysics,UniversityofCalifornia,SanFrancisco Committee:KenA.Dill,MatthewP.Jacobson,VijayS.Pande 1995–1999 B.S.inBiology,CaliforniaInstituteofTechnology UndergraduateresearchwithPaulH.Patterson(experimentalmolecularneurobiology) andJerryE.Solomon(computationalchemistry) Fellowshipsandawards 2017 SiliconTherapeuticsOpenScienceFellowship 2013–2016 LouisV.GerstnerYoungInvestigatorAward 2013–2014 GoogleExacycleforExternalFaculty 2008–2012 QB3-BerkeleyDistinguishedPostdoctoralFellowship,UniversityofCalifornia,Berkeley 2005–2006 IBMPredoctoralFellowship 2005 FrankM.GoyanAwardforoutstandingworkinphysicalchemistry,UniversityofCalifornia,SanFrancisco 2000–2005 HowardHughesMedicalInstitutePredoctoralFellowship Researchoverview Myresearchfocusesonredesigningthewaywedevelopsmallmoleculesforchemicalbiologyanddrugdis- coveryandbringingrigorousatomisticmodelingintothehigh-throughputbiologyandgenomicsera. By combiningnovelalgorithmicadvancestoachieveorders-of-magnitudeefficiencygainswithpowerfulbutin- expensiveGPUhardwareanddistributedcomputingtechnologies,Iamdevelopinganewgenerationoftools andopensourcesoftwarepackagesforpredictingsmallmoleculebindingaffinities,designingsmallmolecules withdesiredproperties,quantifyingdrugsensitivityorresistanceofclinicalmutations,andunderstanding thedetailedstructuralmechanismsunderlyingoncogenicmutations.AsacorememberoftheFolding@home Consortium,mylabharnessesthecomputingpowerofhundredsofthousandsofvolunteersaroundtheworld tostudyfunctionalimplicationsofmutationsandnewopportunitiesfortherapeuticdesignagainstcancer targets.Usingautomatedbiophysicalmeasurements,wecollectnewexperimentaldatatargetedtoadvancethe quantitativeaccuracyofourmethodologies,andgathernewinsightintodrugsusceptibilityandresistancein kinasesandothercancertargets.MyworkmakesextensiveuseofscalableBayesianstatisticalinferencemeth- odsandinformationtheoreticprinciplesfordesigningexperimentsandquantifyingerror.Iampassionateabout openscience,disseminatingsoftwareengineeringbestpractices,andmaximizingresearchreproducibility. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-1 Publications GoogleScholarstatistics:http://goo.gl/qO0JW MyNCBIBibliography:http://goo.gl/e3kjgK h-index:36/i10-index:52/citations:6906(18Feb2018) ∗asteriskdenotesequalcontributions annualcitationcounts(GoogleScholar)–18Feb2018 SubmittedandUnderReview Abl:TKI Co-Crystal Structures Underreview bioRχiv · HauserK,NegronC,AlbaneseSK,RayS,SteinbrecherT,AbelR,ChoderaJD,andWangL AccuratelypredictingtargetedkinaseinhibitorresistancetoclinicalAblmutationsusing alchemicalfree-energycalculations Weshowhowalchemicalfreeenergycalculationscanbeusedtopredictwhetherclinicalpointmutationsinhumankinasedomains conferresistanceorsusceptibilitytotargetedkinaseinhibitors. Abl:axitinib Abl:bosutinib Abl:dasatinib Abl:imatinib Abl:nilotinib Abl:ponatinib PDB: 4WA9 UnPdDerBr: e3vUieEw4 PDB: 4XEY PDB: 1OPJ PDB: 3CS9 PDB: 3OXZ (A) (B) · P1 DFrG-ouit stma2tes1 e34 8 AsWApHU6rg7715 sa2 inhnsgaoantScmoMmT∗ayr75b,5k GiTynre75e9a sotriaoghnkiooiufncGha∗es,meMoipglleernrooWmmTi,icRsse,cssuttrJouScu,tCsuhrfaooldberiroailnoJDghy,i,FabannidEtdSomePreosli+l?geecruMlarAsimulationapproaches,weidentifyasetofhumankinasesthat 2983765 areespeciaAspl7l29y promiscuousbindersofsmallmoleculekinaseinhibitors,andshowthataprototypicalmemberofthisclass,DDR1,achieves DFG-in states thispromiscuitybyvirtueofitsmorestableAsp-DFG-outconformation. (C) DFG-out DFG-out (D) WT D671N WDFTG-out DFG-inDDF6G7-1oNut DFG-in YY775559AA Underreview (kcMaUl/mEo l) 1.24 11..2251 0.79 00..8709 VersYi75o5AnFebrDFuG-inarYy759A16,201DFG8-insubmitt0e dRtou5f0m Eofl npfhotEs1rp00ho aFpte ty,ranM1s5f0e rreud / sre2c0e 0 tt2a50 JM· ,ThompsonA,LakeE,CyphersS,Albanese5oSfK27,HansonSM,BehrJM,ThomasDT,ChoderaJD,andLevinsonNM AdynamicmechanisRmMfSoEr allosteri1c.a9c1tivation1o.f12AurorakinaseAbyactivationloop 1.87 1.11 phosphorylation (kcal/mol) 1.87 1.11 ThroughacombinationofFRET,IR,andEPRlabelingandlarge-scalemoleculardynamicssimulations,weshowthatphorphorylation activatesAurorakinasebyanovelmechanismthatdoesnotsimplycorrespondtoaDFG-outtoDFG-inshift. Prime Inrevision bioRχiv FEP+ · PartonDL,HansonSM,Rodríguez-LaureanoL,AlbaneseSK,GradiaS,JeansC,SeeligerM,ChoderaJD ExpeArnimoepnetnlibraryofhumankinasedomainconstructsforautomateEdxbpaecrtiemrieanltexpression WeengineeralibraryofhumaRnekisniassteadnotm oarinnsowti tchlaussesfiufilcbaatcitoenrialexpressionusinganovelphosphatasecoexpressiontechnique. 131 S N R 131 S N R 0.698 0.902 Accuracy 0.695 0.899 n s 0 5 1 0.690 0.901 n s 1 9 2 o 0.727 0.940 o dicti n 1 U7n6der8review bioRSχpivecificity 0.726 0.719 0.938 0.938 dicti n 0 96 4 Pre r 0 F3a1ssJ,Si9vakDA,C·rooksGSE,eBneasuitcihvaimtypKA,0L.e5im0k 00u.h.55le10rB,and0C.6ho7d 00e.r.6a68J6D Pre r 0 7 12 Quantifyingconfiguration-samplingerrorinLangvevinsimulationsofcomplexmolecularsystems Weaddressa0fu.n6d5amentalquestionregardingwhymoleculardynamicssimulationworksdespitethefactthat0t.h8e4useoffinitetimesteps Accuracy: 0.65 Susceptibleor Neutralor Resistant Accuracy: 0.83 leadstoerror i0nt.h6e4sampledprobabilitydensitiesandpopulations,demonstratinghowtomeasureconfiguratio n0-.s8pa3cesamplingerrorfor animportantclassofLangevinintegratorswidelyusedinbiomolecularsimulation. Figure2. Differentnumericalintegratorsintroducedifferenterrorstructureinphasespace, illustratedinadouble-welUlsnysdteemr.Hreerve,iewweillusbtriaoteRthχetiimvestep-dependentdiscretizationerror introducedbyfourintegratorsona1Ddouble-w·ellpotential[U(x) x6+2cos(5(x+1))]. RossGA,RustenburgAS,Grinaway⌘PB,FassJ,andChoderaJD Thetoprowof2Dcontourplotsillustratesthedifferencebetweenthephase-spacedensityr(x,v) Biomolecularsimulationsunderrealisticsaltconditions sampledatthemaximumtimestepconsidered(Dt=0.7,closetothestabilitylimit)andtheequilibrium densityp(x,v);solidlinesWindeicsahteopwoshitoivwecNonCtoMurCs,cwahnilebdeaushseeddlitnoesimindpilceamteennegtaatinveecfofinctioeunrst.osmostatinmoleculardynamicssimulationstomodelrealisticfluctuationsin Thebottomrowof1Ddensiiotynpelontvsisrhoonwmsteimnetssteapr-odeupnedndbeniotmpeortluercbuatlieons,inanthdesilalmupstlerdatmearhgoinwalthelocalsaltenvironmentaroundbiologicalmacromoleculescandiffer distributioninconfigurationspace,rx,withtheequilibriumdistributionpxisdepictedasasolidblack line.Thesampledmarginasludbisstrtiabunttioianlslyrxfarroemshbowunlkf.orincreasinglylargetimesteps,denotedrDt, depictedbyincreasinglylightdottedlines,forDt=0.3,0.6,...,0.7(arbitraryunits).Inspectingthe contourplotssuggeststhatsomeintegratorsplittings(especiallyVRORV)induceerrorthatfortuitously “cancelsout”whenthedensityismarginalizedbyintegratingoverv,whiletheerrorinotherintegrator splittings(ORVRO,OVRVO)constructivelysumstoamplifytheerrorinconfigurationspace. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-2 Inrevision bioRχiv · WojnarowiczP,DesaiB,ChinY,LimaeSilvaR,OhnakaM,LeeSB,CaoMG,OuerfelliO,XuS,GoldgurY,MillerM,ChaudharyJ,GarlandW, StollerG,AlbaneseSA,SoniR,PhilipJ,HealeyJ,VinagoluR,NortonL,RosenN,HendricksonR,IavaroneA,DannenbergA,ChoderaJD, PavletichN,LasorellaA,CampochiaroP,BenezraR Asmall-moleculepanIdantagonist,AGX51,showsstronganti-tumorandanti-neovascular activity Weidentifythebindingmodeofanewsmall-moleculepan-Idantagonistpriortoitsconfirmationbymassspectrometrycrosslinkingdata. Underreview chemRxiv · GillS,LimNM,GrinawayP,RustenburgAS,FassJ,RossG,ChoderaJD,andMobleyDL BindingModesofLigandsUsingEnhancedSampling(BLUES):RapidDecorrelationofLigand BindingModesUsingNonequilibriumCandidateMonteCarlo NonequilibriumcandidateMonteCarlocanbeusedtoacceleratethesamplingofligandbindingmodesbyordersofmagnitudeover instantaneousMonteCarlo. Underreview · IntlekoferAM,ShihAH,WangB,NazirA,RustenburgAS,AlbaneseSK,PatelM,FamulareC,CorreaFM,ArcilaME,TaylorJ,TallmanMS,Roshal M,PetskoGA,ChoderaJD,ThompsonCB,LevineRL,Stein,EM AcquiredclinicalresistancetoIDHinhibitionthroughintransIDH2mutations ClinicaldoublemutationsactingintransincancerpatientsreceivingIDH2inhibitorsactthroughanovelbiophysicalmechanism. PUBLISHEDANDINPRESS NatureMaterials,inpress DOI · Kdye Kdye KdrSuhgamayY,ShahJK,TdsrcuhgaharganehDF,RoxburyD,Budhathoki-UpretyJ,IȷsikM,MizrachiA,NawalyK,SugarmanJL,BautE,NeimanMR, pure/aq aq/np aq/np pure/aq JohnsonDC,SridharanR,ChuKL,RajasekharVK,ChoderaJD,LoweSW,andHellerDA Quantitativeself-assemblypredictionyieldstargetednanoparticles Adecisiontreebasedonpredictedphysicalpropertiesandandmoleculardescriptorsiscapableofpredictingtheassemblyofdrug/dye nanoparticlesthatcanbeusedintumor-targetedselectivekinaseinhibitortherapytominimizeon-andoff-pathwaytoxicity. Dye in Drug in Pure dye solvent Nanoparticle solvent Pure drug NatureChemicalBiology13:402,2017 DOI a L194 b0.4 CyWWp12h ++TTeppxx22r ((s(cid:111)(cid:111)==11S74..83, nnRss))uffcE,B40ehrJM,Chodde2350r0000aJ3D0 nM, enazymne cdonceLntreatiovni·nsonNM eKinase activity (RFU/min)1102257055050000002 nWpMhT oeWsnzpQy3hm1oe8r 5ycMoMlantcWQDeedn1 1Kt 8rS(aW51tiLio6Tmn)2uflaNormalized activityWKinase activity (RFU/min)Qt00112345i2...1E050o0000000000801n058Q1u- n11(cid:43)p8Mh5+oM es1np0zhQy[o-Tmr1py8C (t)xela+25 QQCQt]cL(ey(cid:43)11o120ds88M8n0 -55.5(lcQ)iC20MLCtee- y1N ns80t+-5-rl+TaiTAACIdArkOaNtetppTNi3)oxnpx0en2x2l2 t i5evltalc0oWWnelcleget12oKinase activity (RFU/min)hisv r--o1uakdTT1234wt0app0000y0oxx5e0000r22ns0000Tn0i rf((iedp0m(cid:111)(cid:111)fi1e==eci5es95WcH0 ..er(Cr492mnTc ep nsnn3AhaMoA),ss2xtoh ))a0esrimnco0p,zQcghyev1ttmoWr8rec2ei5ym ei5ocMvleoa1a0tonta5ecsanaexdnidnn e(tntQrcW-+Correlaion time (ns)baTcT1tagciiTpo8pax)123onoe5xw2o000L205B es lrnl0nixe,WBhncmadWbL1Kinase activity (RFU/min)WTieishyteeou1112(n025p257eWtoQ050505aTaln0000000rH1zat1oif38aprW0lyQ5nbl zny,agL21xM-)8m SpW oQ5e-+ygcy2hTmCnT11ozhpNpl3y8xgsWexmei4.2mp52ae1 xsh2M r scoehomesrCnyKinase activity (RFU/min)3cylleaegsadnHt-112letpi3r050:5tadade000cx0st 4i000(0io,0Cntutr1105yaC050Cues9a000n-y-eo000lspi00att-thesl4io)t+treedesipomm,hdoduQ2r-syo1uel8auc5t0n+ehhMldara t(y1Cpyt-yidQ-sFir7-o1ldoi8rito+e5so)LnTnrn·ipgxn2todD eaogangilnyfOtaeaessLnIeioC-mn,2abRpnF-ulodoehslntmpdyeriddnanoblgtranou@otnreehgxatdoAtywemiSogh,neoylSudrsaretrltkaavoahetggeareSolnae,Gafavtfsueseeeuncrtnrtuspnehn.rrdsirsMeoianrRgulg,ollgCoyshhsshotitaadfetbelsrrlteiaienchJrsDyuand,bcCarsotrttgoirievasvnstaeeJbtRuosi,tonuaildnnibzdnasiTetntihtorwoAnamottruphkesraouotunnhrsdCaaeeBvrelbiehysigh JournalofChemical&EngineeringData62:1559,2017 DOI · MatosGDRandKyuDYandLoefflerHHandChoderaJDandShirtsMRandMobleyDL Approachesforcalculatingsolvationfreeenergiesandenthalpiesdemonstratedwithanupdateof theFreeSolvdatabase WereviewalchemicalapproachestocomputingsolvationfreeenergiesandupdateFreeSolv—themostpopulardatabaseofhydrationfree energiesofneutralmolecules—withmorecomputedandexperimentalproperties. Spine Spine PLoSComputationalBiologyHM13:e1005659T,px22017 DOI EastmanP,SwailsJ,ChodeC-rhealixJD,McGibQ1b85onRC-Thel,ixZhaoY,Beauc·hampKA,WangLP,SimmonettAC,HarriganMP,BrooksBR,andPandeVS OpenMM7:RapiddeveloWatpermentofhighperformancealgorithmsformoleculardynamics Water network network ThelatestversionoftheGPU-acceleratAeudrAmolecpuT28l8arsimulationOpenMMfeaturesavarietyofincrediblyflexiblebutfasttoolsforrapidly PKA prototyping,evaluating,anddeployingnewsimulationalgorithms. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-3 PLoSComputationalBiology12:e1004728,2016 DOI · PartonDL,GrinawayPB,HansonSM,BeauchampKA,andChoderaJD Ensembler:Enablinghigh-throughputmolecularsimulationsatthesuperfamilyscale Wedemonstrateanewtoolthatenables—forthefirsttime—massivelyparallelmolecularsimulationstudiesofbiomoleculardynamicsat thesuperfamilyscale,illustratingitsapplicationtoproteintyrosinekinases,animportantclassofdrugtargetsincancer. JournalofClinicalInvestigation126:3529,2016 DOI · XuJ,PhamCG,AlbaneseSK,DongY,OyamaT,LeeCH,Rodrik-OutmezguineV,YaoZ,HanS,ChenD,PartonDL,ChoderaJD,RosenN, ChengEH,andHsiehJJ Mechanisticallydistinctcancer-associatedmTORactivationclusterspredictsensitivityto rapamycin WeusemassivelyparalleldistributedmolecularsimulationsonFolding@hometoprobethemechanismactivatingmutationsofthemTOR kinaseidentifiedinclinicalpopulations. bioRxiv preprint first posted online June 29, 2015; doi: http://dx.doi.org/10.1101/021659; The copyright holder for this preprint is the author/funder. 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￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿Fvlaop((artcbaijbiposc￿sthemwtadwttsmeearhuoiihoeionerfy￿￿liovaeaIomfcmcnhiaovisenineulrtGaalinnsBn￿mreveztsnegesztlhesnstonbidelsituridtitc-irityvcb.rurleinrnatintetvrracaai?eohbaantolzeeaeahtesyilnadgtagggnitxses3bilfabgmpiasivTd’rienrdwnesttoioda-s.ubEcbutkipdlemlf,ivfaagentfuhioodekfeercitvnm=otilociaarcaanrohayrntrsieiatenodiaoiorbhdsoz￿soicrtnhmteBssspgrvtf2aterieoiwamieoindmmeituamaeiaiseaiaaiwc0aat.csaqraecNtsnvcstslhatns0aneeatiahafpserviitinhuidtcUiulsaeato0oltnowqtnn-toceiridhloaogiithvanineetsd⌧enl↵etdvnlnugtvicieaghihilalitsmnocdsve0acanklabetgiitffeftfpetreydetoteeolouhrrloiogrnrvielrii(hurs,ioerqiodonsis￿ebraaa0taaefovroqaneec￿i(iminumttnbnriretnsfismhaaewd(idus⌧￿hehinatiifotrcbcFaoiemeaoiloiu0￿sae)atrerirttecemineuflqnirtsiourcerfbinaiatgltiaooredahmotoeulurciissrophttlecreuaslu0t,endr￿leaeietnilrra(fkliytygaqmml⇠ytpplagiirriianoi(i.rtaaxcnmifoesecebustfilt-lldoiomdonueearoimuaitxtaednroiodirHc9emenandlieitrlspf￿rairllnaiaeoptuivpe0osgot(sbotgvteaeeioaetn1eytinintlniainsenc￿rae⌧iwtcpntdioss0qsi8sguvdaihc,ohg,leiotmtctt)eutntluomu0laabsta0r.s￿uoefpiheeieotomwirric0imoatntruoatImmie)lauwemeroeeuuitfriaciiarlteoiaenlambrp⌧delsofsslsilatrlusapsmyennelcd)bhrnrflilt)aof⌧itoteelijyna.ibenipyi)ngtecveadeteaicelxi)ms,blvmthanigchaaeatsrcetAeeersseeleizctceoa0yicoeainlettrseacsa￿0oad.Eeotomliaeoicrwrspntyndzbteagrnttirqmiit)nsorebibalcc?iseeritsanrc[heostyizsiotwetmdhhcme￿iitimpqse,ecae0tarsnoamebsi￿Waonodaeeeeae,xudotttsp.opnsTaitbpdnifhacsi,rrewnimbiecnhmtofsseancu]eeln,dedelaToee0,ieoeteep.enbsoeyltbtatiar0cnrlqFadtsndlathgDendsawealtrxyrrog,hislieetdtutv0rkmddnjaiagiionekfwmhteeieonesmaled,armiurtttrnnesfcldvweaogeiogroiliasswo[rpirotipjosactolaabettteezneomthvtso￿￿￿￿￿￿￿￿u￿ctra￿ehwfgwti0cin￿t￿￿￿￿￿￿￿e￿rvtrr￿seorbte￿￿￿￿￿￿￿￿￿et￿ri￿thdaeaccea,iauiasmhgnfthegileearartia1aqoitosbaewuetTett0anmmslthethnNadgyb0msfauti.ntenlscd0t.aiotisgerntemieepeoi�teneo]ihercoiognBcecpgo[evaaot——Bonrorrcfadnsr4iin￿iinh↵uleenehleyg0eeeeyssstssssr.￿t--tf---eft,windt,aho,h￿diliancDiot￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿u￿￿￿￿￿￿T￿￿￿￿￿￿a￿sRdJMwpJBMTlt￿￿￿￿￿￿h￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿s￿￿￿￿￿￿￿￿￿￿ig]pni￿￿￿m￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿￿e￿￿￿.oniioictlseuegentmtatibrtpbepotaoatfgcnepuvgseoootpsnHoc￿teiihhhinueoarcvaeooessllbapfso?iiiemoototoilotaAparaslriqrreeettasrinTAAeayrsrtioozsttIanniicrnilliisnsslincyeiuhcfselilitopemmqluuaoncoehlisaesrtos.omawisi,lghtlctaeerstbPioiortdraohsitrtuutbpetsomitywritramemS,eleaaflualsyerteos7nslnnecmeateim0lilsutemtaohcentgirstdkietlttytesspotirrrfrdhlehsmu,iisooseetehmtogiliogenddcaaeirobesiooagleaotraseoontplilddegtuilefhsivrcpsnasanvidr.ePmennoiheqpofcpcanipeadflcntatantscaeiatgnretacda4ebahccysatxdlufilesapwoiiecotiotaerlxmmrhoheebfuo[lruesucatiatiolccidxatiluipsotnederdrnlidnmyhrolnairtitulslaamemampt0ynpeeeaiittieaa-eurfsi,sctpbroucvbonnn,ecoasurch,o,uohawacttlep—rreiturheaioborhltctbcmarnrlTicicdusrsttwsectcyoimuOahnaaidaennoelyalludlfewelifierlhiataieedtrrAhony]mwtnmsttttfiruiyasbyrgpreonee—nilariioscadsneehieifdPnenrieoozeeegnffnnoortd,trettcacuenoeeloodtvraSlsewh.ieIifdeloerrsrtnheaaignsdronerorooosst.lfnclfeiiIsItwesuatt￿iunpaalgomerAiMetwruhvpfMfmsibvsncoofsstucbtavlntfebnstnAttileeaiaspmiileffasiehioheirebcwhUmngileinlwinsMiormserrabwfyaiorsplcdcreeteoilsrowdhsiytnutdgLmipacdicteeohfbhieinistrtrintheac.chuKreohue￿iaArtolosrvgeetgnnheSiveCPdaeeeohkrarnhAoenneasaetTtwsc.ltsrlianaswiidfceprnbe￿sndcsbi—eaEsisedplecrnotsIneiepmrfioreosmyitronGlttOetlro,—odreetiiqatAeds[waetrrohgnewiymehczbraleettrpu￿nwlthmssumraNltauro.easecaihwchtn￿ae.pwjeeeee—rDdoeutaiydcehbueptglfco.]F￿ngaitrriseuresuoDraa.aoeeshresehe￿oecd,hstsrulsse(pixbnstornvhsslOsodytnpEiegaraseumtpadtiuiiaauuwoauprlcoieumilmotaoaoecaTyaotcBevtocadmnvcciesltarootna￿oaaoxlwueamrtvgAssirhhap￿kianenpede----fanlulaotsyntiraaapaobIriatphgcosseintcisldLtplglchnemilselslyoylrnuaahttieeeerioelcSlseiapodrteaitccsiiha.nyossbtsetrtmoeebiamipsonc,nahwceiocbhtceiacwthltotnHannialhffarest:cahnmarmlcfcpencreond,tneumitsctginhoyleeodlhtasahseerrtth.xirdairecsktwaioorhhofEmnatntiqdpvieonetIo—oittdblnimenionqtelrociaeuaeitnyfcettsrtmaeaceeesioho.Jzvirpetwirdtn￿cltGtlsiastndoqqlaiouhe￿s—meeiraiieehcmoeeilasieJa￿blzntauuedcceeMrtsyhhntmelhrdfitinl,gfp.CHjireiiaeetenlmebeseeemell,eaia,soiurciipvwnruihsuoogshncnrmxebbnenttmttanattpemtrctmibtLp￿atwchcirrltaviseiolmoitnehw,fhmaahn,￿eiyilwwiithr.r—htdnAarsstgo.ottieeaaciiedayhotyegohetuRtaiiieebiuirtmcnntoooaalanehixncsnaorrrmaegalcetiioliddnnnnngeeeeeeessatt------)flmyieudsxdmBsfidsmaie,fteebciOerdsnlvaudneotrelnebMsrtlnmmiwoyuat-cpoyroiwrBngehdlctaeeAehac1hmcnDlrSati9ueein,,lteawlBl9MigeacTrran:atpor1ykhegdlbrlDc2eyotileihoenteC9asyroncsgstI1mciD,oiqrpogK2moLuialnorb,,etfrpo,a2oMtsueun3ao0nimtdtn0tfelL1ieCeort:poi9-ha5hndrmgnseeo4uKau·ddSi5i,rcDdtieAseac,aoernttMc2Oaidideynac0JPrcCgfIDruL1lfifhofcg5ro6ohcehddeerei·exixecevseeDariennarnegceOfinJetirDs-,sgewebI.i.fleuadosttesotrrhf:tdetNhribsaeteenrnsiaSbcfetuhArtmlibMioaqenrtuPkwcioinLedeeg5fnfidaccnaeiqdhenuniamestlsoilptuferoisoner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SivakDA,ChoderaJD,andCrooksGE Timesteprescalingrecoverscontinuous-timedynamicalpropertiesfordiscrete-timeLangevin integrationofnonequilibriumsystems Wederiveasimple,easy-to-implementLangevinintegratorthathasuniversallyusefulpropertiesinmolecularsimulations. PhysicalReviewX4:011020,2014 DOI · PrinzJ-H,ChoderaJD,andNoéF Spectralratetheoryfortwo-statekinetics Wepresentanewmathematicalframeworkforunifyingvarioustwo-stateratetheoriespresentedinthephysicalchemistryliterature overmanydecades,andprovideaquantitativewaytomeasurereactioncoordinatequality. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-4 JournalofComputerAidedMolecularDesign27:989–1007,2013 DOI · WangK,ChoderaJD,YangY,andShirtsMR IdentifyingligandbindingsitesandposesusingGPU-acceleratedHamiltonianreplicaexchange moleculardynamics Weshowhowboundligandposescanbeidentifiedevenwhenthelocationofthebindingsitesareunknownusingthemachineryof alchemicalmodernfreeenergycalculationsongraphicsprocessors. JournalofPhysicalChemistryB117:9956–9972,2013 DOI · WangL-P,Head-GordonTL,PonderJW,RenP,ChoderaJD,EastmanPK,MartinezTJ,andPandeVS Systematicimprovementofaclassicalmolecularmodelofwater Wateristhemostimportantmoleculeinbiology,andaccuratetreatmentofitsinteractionsiscriticaltoaccuratemodelingfordrug discovery.Whilepolarizablemodelsofwatercanachieveveryhighaccuracies,theyarebothdifficulttoparameterizeandexpensiveto employ.Here,weshowhowahighqualityinexpensivepolarizablemodelofliquidwatercanbederivedusinganautomated parameterizationengine. PhysicalReviewX3:011007,2013 DOI · SivakDA,ChoderaJD,andCrooksGE Usingnonequilibriumfluctuationtheoremstounderstandandcorrecterrorsinequilibriumand nonequilibriumdiscreteLangevindynamicssimulations Allmoleculardynamicssimulationsintroduceerrorintothesampleddistributionbyvirtueofthefinitetimestepusedtointegratethe equationsofmotiononadigitalcomputer.Whiletraditionalapproachestoanalyzingthiserrorareextremelycomplicated,weshowhow interpretingfinite-timestepintegratorsasaformofnonequilibriumdrivingleadstosimple,straightforwardschemesforassessingthe impactoftheseerrors,aswellascorrectingforthem. JournalofChemicalTheoryandComputation9:461,2012 DOI · EastmanP,FriedrichsMS,ChoderaJD,RadmerRJ,BrunsCM,KuJP,BeauchampKA,LaneTJ,WangL,ShuklaD,TyeT,HoustonM,StichT,Klein C,ShirtsMR,andPandeVS OpenMM4:Areusable,extensible,hardwareindependentlibraryforhighperformancemolecular simulation InexpensiveconsumerGPUspromisea100-foldincreaseinsimulationpowerbyproblemsthatcaneffectivelyexploittheirhighly specializedstructure.Here,wedescribethelatestadvancesinanextremelyhighperformance,open-source,extensibleGPU-accelerated libraryandtoolkitformolecularsimulation. BiophysicalJournal103:1490,2012 DOI · ElmsPJ,ChoderaJD,BustamanteCJ,MarquseeS Thelimitationsofconstant-force-feedbackexperiments Popularconstant-force-feedbacksingle-moleculeexperimentscancausesevereartifactsinsingle-moleculeforcespectroscopydata.We demonstrateasimplealternativethateliminatestheseartifacts. ProceedingsoftheNationalAcademyofSciences109:3796,2012 DOI · ElmsPJ,ChoderaJD,BustamanteC,MarquseeS Themoltenglobulestateisunusuallydeformableundermechanicalforce Wemeasurethephysicalpropertiesofthemoltenglobulestateofapo-myoglobin,andshowthatitisunusuallydeformablecomparedto typicalproteinnativestates. JournalofChemicalTheoryandComputation8:3445,2012 DOI · PiteraJWandChoderaJD Ontheuseofexperimentalobservationstobiassimulatedensembles Weshowhowtheconceptofmaximumentropycanbeusedtorecoverunbiasedconformationaldistributionsfromexperimentaldata, andhowthisconceptrelatestothepopular‘ensemblerefinement’schemesforNMRdataanalysis. Science334:1723,2011 DOI · KaiserCM,GoldmanDH,ChoderaJD,TinocoI,Jr.,andBustamanteC Theribosomemodulatesnascentproteinfolding Usingsingle-moleculeforcespectroscopy,weshowhowtheribosomeitselfmodulatesthefoldingdynamicsofnascentproteinchains emergingfromtheexittunnel. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-5 PhysicalReviewLetters107:098102,2011 DOI · ChoderaJDandPandeVS Splittingprobabilitiesasatestofreactioncoordinatechoiceinsingle-moleculeexperiments Wedemonstrateasimpletestforidentifyingpoorreactioncoordinatesinsingle-moleculeexperiments. AnalyticalBiochemistry414:297,2011 DOI · TellinghuisenJTandChoderaJD Systematicerrorsinisothermaltitrationcalorimetry:Concentrationsandbaselines Awordofcautionaboutlargeerrorsinisothermaltitrationcalorimetrymeasurementsarisingfromligandconcentrationerrors. JournalofChemicalPhysics134:024111,2011 DOI · MinhDDL,ChoderaJD Estimatingequilibriumensembleaveragesusingmultipletimeslicesfromdrivennonequilibrium processes:Theoryandapplicationtofreeenergies,moments,andthermodynamiclengthin single-moleculepullingexperiments Wederiveanewestimatorforestimatingequilibriumexpectationsfromnonequilibriumexperiments,andshowhowitcanbeusedto estimateavarietyofusefulquantitiesinsimulatedsingle-moleculeforcespectroscopyexperiments. ProceedingsoftheNationalAcademyofSciences108:E1009,2011 DOI · NilmeierJP,CrooksGE,MinhDDL,andChoderaJD NonequilibriumcandidateMonteCarloisanefficienttoolforequilibriumsimulation WepresentasignificantgeneralizationofMonteCarlomethodsthatprovideanenormouslyusefultoolforenhancingtheefficiencyof molecularsimulationsandenablingmoleculardesign. JournalofChemicalPhysics134:244108,2011 DOI · PrinzJ-H,ChoderaJD,PandeVS,SmithJC,andNoéF Optimaluseofdatainparalleltemperingsimulationsfortheconstructionofdiscrete-state Markovmodelsofbiomoleculardynamics Wedemonstratehowmultitemperaturedatafromparalleltemperingsimulationscanbeusedtoconstructfullytemperature-dependent modelsofthedynamicsofbiomolecularsystems. JournalofChemicalPhysics134:244107,2011 DOI · ChoderaJD,SwopeWC,NoéF,PrinzJ-H,ShirtsMR,andPandeVS Dynamicalreweighting:Improvedestimatesfordynamicalpropertiesfromsimulationsat multipletemperatures Wedescribehowreweighingtechniquescanprovideoptimalestimatesoftemperature-dependentdynamicalpropertiesfromsimulations conductedatmultipletemperatures. ProceedingsoftheNationalAcademyofSciences108:4822,2011 DOI · NoéF,DooseS,DaidoneI,LöllmannM,SauerM,ChoderaJD,andSmithJC Dynamicalfingerprints:Atheoreticalframeworkforunderstandingbiomolecularprocessesby combinationofsimulationandkineticexperiments Wepresentanewframeworkforcomparingessentialfeaturesofthedynamicsbetweenexperimentandsimulationtoidentifythekinetics processescontributingtoindividualrelaxationtimescalesinperturbation-responseorcorrelationspectroscopyexperiments. JournalofChemicalPhysics135:194110,2011 DOI · ChoderaJDandShirtsMR ReplicaexchangeandexpandedensemblesimulationsasGibbssampling: Simpleimprovementsforenhancedmixing Weshowhowasimplechangetothewayexchangesarehandledinthepopularreplica-exchangesimulationmethodologycan astronomicallyincreaseefficiencyatnoincreaseincomputationalcost. JournalofPhysicalChemistryB114:2549,2010 DOI · PonderJW,WuC,RenP,PandeVS,ChoderaJD,MobleyDL,SchniedersMJ,HaqueI,LambrechtDS,DiStasioRAJr.,Head-GordonM,Clark GNI,JohnsonME,andHead-GordonT CurrentstatusoftheAMOEBApolarizableforcefield TheAMOEBApolarizableforcefieldisabletoreproduceadiversesetofphysicalchemicalphenomenontohighaccuracy. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-6 JournalofChemicalPhysics133:105102,2010 DOI · ChoderaJDandNoéF ProbabilitydistributionsofmolecularobservablescomputedfromMarkovmodels. II.Uncertaintiesinobservablesandtheirtime-evolution AsimpleBayesianapproachforthemodelingofstatisticaluncertaintiesinkineticandequilibriumquantitiescomputedfromMarkov statemodelsofbiomoleculardynamics. BiophysicalJournal98:3062,2010 DOI · AdelmanJL,ChoderaJD,KuoIW,MillerTF,andBarskyD ThemechanicalpropertiesofPCNA:ImplicationsfortheloadingandfunctionofaDNAsliding clamp MolecularsimulationsofthePCNAclampresponsibleforDNApolymeraseprocessivityshowasurprisinglysmallenergeticpenaltyforthe deformationrequiredforclamploading.Featuredonissuecover. JournalofChemicalPhysics131:045106,2009 DOI · BacalladoS,ChoderaJD,andPandeVS BayesiancomparisonofMarkovmodelsofmoleculardynamicswithdetailedbalanceconstraint ABayesianschemeforcomparingstatespacedecompositionsforMarkovstatemodelsofbiomoleculardynamicsthatincorporatesthe factthatphysicalsystemsmustobeydetailedbalance.ThispaperutilizesrecentresultsfromMarkovchaintheoryonedge-reinforced randomwalks. JournalofChemicalPhysics131:134110,2009 DOI · MinhDDL,ChoderaJD Optimalestimatorsandasymptoticvariancesfornonequilibriumpath-ensembleaverages Wederiveanoptimalestimatorandcorrespondingstatisticaluncertaintiesforinferringexpectationsofbidirectionalnonequilibrium processes.Theseestimatorshavewidespreadapplicabilityinsingle-moleculebiophysicalforce-spectroscopyexperimentsand nonequilibriummolecularsimulations. JournalofChemicalPhysics129:124105,2008 DOI · ShirtsMR,ChoderaJD Statisticallyoptimalanalysisofsamplesfrommultipleequilibriumstates Wepresentahighlygeneral,statisticallyoptimalapproachforproducingestimatesoffreeenergiesandequilibriumexpectationsfrom multiplesimulationsthatprovablyextractsallusefulinformationfromthedata. JournalofMedicinalChemistry51:769,2008 DOI · NichollsA*,MobleyDL*,GuthrieJP,ChoderaJD,andPandeVS Predictingsmall-moleculesolvationfreeenergies:Ablindchallengetestforcomputational chemistry Ablindevaluationoftheaccuracyofalchemicalfreeenergymethodsforcomputinggas-to-watertransferfreeenergies(solvationfree energies)ofsmallmoleculesdemonstratesthatmodernforcefieldsarelikelysufficientlyaccuratetobeusefulindrugdesign. JournalofPhysicalChemistryB112:938,2008 DOI · MobleyDL,DillKA,andChoderaJD Treatingentropyandconformationalchangesinimplicitsolventsimulationsofsmallmolecules Anquantitativeexaminationofhowmuchconformationalentropycontributestohydrationfreeenergiesofsmallmolecules,with implicationsforligandbinding. JournalofPhysicalChemistryB111:13052,2007 DOI · ShirtsMR*,MobleyDL*,ChoderaJD,andPandeVS Accurateandefficientcorrectionsformissingdispersioninteractionsinmolecularsimulations Weidentifyamajorsourceofsystematicerrorinabsolutealchemicalfreeenergycalculationsofligandbindingandshowhowasimple procedurecaninexpensivelyandaccuratelyeliminateit. JournalofPhysicalChemB111:2242,2007 DOI · MobleyDL,DumontE,ChoderaJD,BaylyCI,CooperMD,andDillKA Comparisonofchargemodelsforfixed-chargeforcefields:Small-moleculehydrationfree energiesinexplicitsolvent Wecompareanumberofpopularmethodsforderivingchargemodelsforsmallmolecules,derivinglessonsaboutbestpracticesfor accuratesimulations. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-7 JournalofMolecularBiology371:1118,2007 DOI · MobleyDL,GravesAP,ChoderaJD,McReynoldsAC,ShoichetBK,andDillKA Predictingabsoluteligandbindingfreeenergiestoasimplemodelsite Weshowhowalchemicalfreeenergycalculationsarecapableofaccurateblindpredictionofsmall-moleculebindingaffinitiestoasimple modelproteinbindingsite. JournalofChemicalandTheoreticalComputation3:1231,2007 DOI · MobleyDL,ChoderaJD,andDillKA Confine-and-releasemethod:Obtainingcorrectbindingfreeenergiesinthepresenceofprotein conformationalchange Wepresentageneralschemeforobtainingcorrectligandbindingaffinitieswhenproteinconformationalchangeisimplicatedinligand binding. JournalofChemicalPhysics126:155101,2007 DOI · ChoderaJD*,SinghalN*,SwopeWC,PiteraJW,PandeVS,andDillKA AutomaticdiscoveryofmetastablestatesfortheconstructionofMarkovmodelsof macromolecularconformationaldynamics Proposingoneofthefirstautomatedalgorithmsfordiscoveringkineticallymetastablestatesofbiomoleculesfrommolecularsimulations, thispapershowshowmanybiomoleculescanpossessnumerousdistinctlong-livedconformationalstateseventhoughthetheequilibrium populationsofthesestatesmaytoosmallforstandardstructuralbiologytechniquestodetect. ProceedingsoftheNationalAcademyofSciences104:11987,2007 DOI · OzkanSB,WuGA,ChoderaJD,andDillKA ProteinFoldingbyZippingandAssembly Areviewoftheutilityoftheproposedzippingandassemblymechanismfortheconcomitantformationofsecondaryandtertiary structureinproteinfoldingforpredictingfoldingpathwaysandnativestructures. JournalofChemicalTheoryandComputation3:26,2007 DOI · ChoderaJD,W.C.Swope,J.W.Pitera,C.Seok,andK.A.Dill Useoftheweightedhistogramanalysismethodfortheanalysisofsimulatedandparallel temperingsimulations Theweightedhistogramanalysismethod(WHAM),amainstayofmoleculardynamicssimulationanalysis,isthoroughlyexplainedand modernizedfortheanalysisofsimulatedandparalleltemperingsimulationdata. JournalofChemicalPhysics125:084902,2006 DOI · MobleyDL,ChoderaJD,andDillKA Ontheuseoforientationalrestraintsandsymmetrycorrectionsinalchemicalfreeenergy calculations Weillustratehoworientationalrestraintscanbeusedtogreatlyreducethecomputationaleffortinalchemicalcalculationsofligand bindingfreeenergies,andclarifyhowsymmetrycorrectionsarenecessarywhenmoleculescontainsymmetricorpseudosymmetric substituents. MultiscaleModelingandSimulation5:1214,2006 DOI · ChoderaJD,SwopeWC,PiteraJW,andDillKA Long-timeproteinfoldingdynamicsfromshort-timemoleculardynamicssimulations Weshowhowthelong-timedynamicsofbiomolecularsystemscanberecapitulatedfromstatisticscollectedfromshortmolecular simulationssamplingtransitionsbetweenkineticallymetastablestates. JournalofComputationalChemistry24:89,2003 DOI · SeokC,RosenJB,ChoderaJD,DillKA MOPED:Methodforoptimizingphysicalenergyparametersusingdecoys Weproposeanewwaytooptimizeparametersforaphysicalenergyfunctionusingdecoystructuresforproteinfoldingstudies. JournaloftheAmericanChemicalSociety123:12837,2001 DOI · LeeTS∗,ChongLT∗,ChoderaJD,andKollmanPA Analternativeexplanationforthecatalyticproficiencyoforotidine5’-phosphatedecarboxylase AcombinedQMandMDanalysisofpotentialplausiblemechanismstoexplaintheenormouscatalyticaccelerationofoneofthemost proficientenzymesknown. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-8 ReviewsandCommentaries CurrentOpinioninStructuralBiology25:135,2014 DOI · ChoderaJDandNoéF Markovstatemodelsofbiomolecularconformationaldynamics AreviewofexcitingrecentdevelopmentsinthestochasticmodelingofbiomoleculardynamicsusingtechniquesIoriginallyco-developed tostudyproteinfolding. AnnualReviewsinBiophysics42:121,2013 DOI · ChoderaJDandMobleyDL Entropy-enthalpycompensation:Roleandramificationsforrationalliganddesign Entropy-enthalpycompensationislikelyauniversalphenomena,butnotassevereaswidelythought,andirrelevantfordrugdiscovery andliganddesign. CurrentOpinioninStructuralBiology21:150,2011 DOI · ChoderaJD,MobleyDL,ShirtsMR,DixonRW,BransonKM,andPandeVS Freeenergymethodsindrugdiscoveryanddesign:Progressandchallenges Areviewofcurrentopportunitiesandchallengesforalchemicalfreeenergycalculationsindrugdiscoveryanddesign. JournalofChemicalPhysics134:174105,2011 DOI · PrinzJH,WuH,SarichM,KellerB,FischbachM,HeldM,ChoderaJD,Schütte,andNoéF Markovmodelsofmolecularkinetics:Generationandvalidation CurrentbestpracticesforthegenerationandvalidationofMarkovstatemodelsfordescribingthestochasticdynamicsofbiomolecular systems. ProceedingsoftheNationalAcademyofSciences108:12969,2011 DOI · ChoderaJDandPandeVS TheSocialNetwork(ofproteinconformations) Anewmethodologyformappingproteinconformationalspacesisreminiscentofhowweusetwo-dimensionalmapstonavigatea three-dimensionalworld. AnnualReportsinComputationalChemistry3:41,2007 DOI · ShirtsMR,MobleyDL,ChoderaJD Alchemicalfreeenergycalculations:Readyforprimetime? Areviewofcurrentalchemicalfreeenergymethodologiesandtheirpotentialforuseindrugdiscoveryandliganddesign. CurrentOpinioninStructuralBiology17(3):342,2007 DOI · DillKA,OzkanSB,WeiklTR,ChoderaJD,andVoelzVA Theproteinfoldingproblem:Whenwillitbesolved? Areviewofthecurrentstateoftheproteinfoldingproblem. JOHND.CHODERA-SLOANKETTERINGINSTITUTE-9 Preprintsaheadofsubmission Preprintaheadofsubmission bioRχiv · BoyceSE,TellinghuisenJT,andChoderaJD Avoidingaccuracy-limitingpitfallsinthestudyofprotein-ligandinteractionswithisothermal titrationcalorimetry Wedemonstratehowtoavoidaccuracy-limitingproblemsinstandardisothermalcalorimetryexperimentsaswellascapturetheprimary sourcesofuncertaintyinthermodynamicparameters. Preprintaheadofsubmission arχiv · ChoderaJD,NoéF,HinrichsNS,KellerB,ElmsPJ,KaiserCM,Ewall-WiceA,MarquseeS,andBustamanteC BayesianhiddenMarkovmodelanalysisofsingle-moleculebiophysicalexperiments WepresentaBayesianhiddenMarkovmodelanalysisschemethatallowsbiomolecularconformationaldynamics—andthe correspondinguncertaintyduetolimiteddata—tobeinferredfromsingle-moleculetrajectories.Thisapproachwasdevelopedfora single-moleculestudyexaminingfoldingdynamicsofnascentproteinsexitingtheribosome[Science334:1723,2011·DOI]. Preprintaheadofsubmission arχiv · ChoderaJD,ElmsPJ,SwopeWC,PrinzJ-H,MarquseeS,BustamanteC,NoéF,andPandeVS Arobustapproachtoestimatingratesfromtime-correlationfunctions Wepresentasimple,robustapproachtoestimatingtwo-staterateconstantsfromexperimentalorsimulationdata. ScientificAdvisoryBoards 2013– Schrödinger,LLC Peerreviewerforscientificjournals Bioinformatics,Biopolymers,ChemicalPhysics,Computation,DrugDiscoveryToday,EuropeanBiophysics Journal,Entropy,InternationalJournalofMolecularSciences,JournaloftheAmericanChemicalSociety,Journal ofChemicalTheoryandComputation,JournalofComputer-AidedMolecularDesign,JournalofComputational Chemistry,JournalofComputationalPhysics,JournalofPhysicalChemistry,JournalofPhysicalChemistry Letters,MolecularPhysics,MultiscaleModeling&Simulation,NatureChemistry,NatureCommunications, NaturePhysics,PacificSymposiuminBiocomputing,PLoSComputationalBiology,PLoSOne,Proceedingsof theNationalAcademyofSciences,ScientificReports,Structure AcademicService MSKCC HighPerformanceComputingSteeringCommittee 2012–2015 Member,Co-administratorofMSKCCGPUHPCresource GraduatePrograms 2013– PrograminPhysiology,Biophysics,andSystemsBiology(PBSB) Tri-InstitutionalPhDPrograminChemicalBiology(TPCB) 2013– Tri-InstitutionalPrograminComputationalBiologyandMedicine(CBM) 2013– GerstnerSloanKetteringGraduateProgram(GSK) 2015– JOHND.CHODERA-SLOANKETTERINGINSTITUTE-10

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We show how alchemical free energy calculations can be used to predict whether clinical point mutations in human kinase domains confer resistance Under review ·. Ruff EF, Muretta JM, Thompson A, Lake E, Cyphers S, Albanese SK, Hanson SM, Behr JM, Thomas DT, Chodera JD, and Levinson NM.
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