Molecular Dynamics Simulation of Folding and Diffusion of Pr

A novel combination of discontinuous molecular dynamics and the Langevin equation, together with an intermediate-resolution model, are used to carry out long (several $\mu$s) simulation and study folding transition and transport of proteins in slit nanopor

arXiv:cond-mat/0703387v2 [cond-mat.soft] 25 Jan 2008

MolecularDynamicsSimulationofFoldingandDi usionofProteinsinNanopores

LeiliJavidpour,aMuhammadSahimi,b, andM.RezaRahimiTabara,c

b

Dep.ofPhysics,SharifUniversityofTechnology,Tehran11365,Iran

MorkFamilyDepartmentofChemicalEngineering&MaterialsScience,UniversityofSouthernCalifornia,LosAngeles,

California90089-1211,USA

c

CNRSUMR6529,ObservatoiredelaCo ted’Azur,BP4229,06304NiceCedex4,France

AnovelcombinationofdiscontinuousmoleculardynamicsandtheLangevinequation,togetherwithanintermediate-resolutionmodel,areusedtocarryoutlong(severalµs)simulationandstudyfoldingtransitionandtransportofproteinsinslitnanopores.Bothattractive(U+)andrepul-sive(U )interactionpotentialsbetweentheproteinsandtheporewallsareconsidered.NearthefoldingtemperatureTfandinthepresenceofU+theproteinsundergoarepeatingsequenceoffolding/partially-folding/unfoldingtransitions,whileTfdecreaseswithdecreasingporesizes.TheoppositeistruewhenU ispresent.Theproteins’e ectivedi usivityDiscomputedasafunctionoftheirlength(numberoftheaminoacidgroups),temperatureT,theporesize,andtheinteractionpotentialsU±.FarfromTf,Dincreases(roughly)linearlywithT,butduetothethermal uctua-tionsandtheire ectontheproteins’structurenearTf,thedependenceofDonTinthisregionisnonlinear.Undercertainconditions,transportofproteinsinsmallerporescanbefasterthanthatinlargerpores.

PACS:87.15.Aa,83.10.Mj,http://doc.guandang.net,87.15.Vv,87.83.+a

a

Proteins’importancetobiologicalsystemscannotbeoverstated[1]:asenzymestheycatalyzeandregulatecells’activities;tissuesaremadeofproteins,whileasantibodiesproteinsareavitalpartoftheimmunesys-tem.Proteinswithglobularstructurefoldintocompactandbiologicallyactivecon gurations,andanimportantproblemisunderstandingthemechanismsbywhichtheyattaintheirfoldedstructure,andfactorsthatcontributetothefolding[2–4].Suchunderstandingisimportantduetodebilitatingillnesses,suchasAlzheimer’sandParkinson’sdiseases,thatarebelievedtobetheresultofaccumulationoftoxicproteinaggregates[5–8],aswellastotheindustrialproductionofenzymesandtherapeuticproteinsbasedontheDNArecombinantmethod[9].Whilethethree-dimensional(3D)structureofnativeproteinsiscontrolledbytheiraminoacidsequence[2–4],theirtransportpropertiesandthekineticsoftheirfoldingdependonthelocalenvironment.But,whereasproteinfoldingindilutesolutionsunderbulkcondition,typicallyusedininvitrostudies,isrelativelywell-understood,themoreimportantproblemofproteinfoldinginacon nedmediumisnot.Theenvironmentinsideacellinwhichproteinsfoldiscrowded,withthevolumefractionofthecrowdingagents(suchasRNA)maybe0.2-0.3.Thus,evenintheabsenceofinteractionsbetweenproteinsandothercellularmolecules,theirmovementinsidethecellislimited.Thelimitationa ectsproteins’stability.Exper-imentsindicated[10]thatcon nementoftenstabilizestheproteins’nativestructure[11],denaturestheminthelimitedspaceofthecagemodel, rstsuggestedbyAn nsen[2–4],andacceleratesfoldingrelativetothatinbulksolutions.Studiesofproteinsofdi erentnativearchitecturesincylindricalnanporesindicated[12]that,invivofoldingisnotalwaysspontaneous;rather,asubsetofproteinsmayrequiremolecularchaperones.

Protein(enzyme)immobilizationusingporoussolidsupport,viaadsorption,encapsulation,andcovalentlink-ing,hasbeenusedforalongtime[13,14].Suchpracti-calapplicationsasbiocatalysis[15]andbiosensorsalsoentailnotonlybetterunderstandingofthefoldingincon nedmedia,butalsotransportofproteinsinsuchmedia.Atthesametime,proteinpuri cationusingnanoporousmembranesisalsogainingattention[16].SiCnanoporousmembranes[17]allow[18]di usionofproteinsupto29000Daltons,butexcludelargerones.Despitethefundamentalandpracticalsigni canceoftransportofproteinincon nedmedia,thereiscurrentlylittleunderstandingofthephenomenon.

Thegoalofthispaperistwofold.First,weusemolec-ulardynamics(MD)simulationtostudyproteinfoldingandstabilityinslitnanopores.Second,weutilizeanovelcombinationofMDsimulationandtheLangevinequa-tion(LE)tostudyproteintransportinthenanopores.Toourknowledge,ourcombinationoftheMDsimula-tionandtheLEhasneverbeenproposedbefore,norhastherebeenanysimulationoftransportofproteinsinnanopores.Forsuchimportantpracticalapplicationsasmembranepuri cation,biocatalysis,andsensors,thetransportofproteinsinnanoporesisofutmostimpor-tance.Aslitnanoporeisareasonablemodelforthetypeofporesthatoneencountersinsuchapplications[15–18]and,despiteitssimplicity,itmightalsobeareasonablemodelfortheporesinbiologicalmembranes.

SomeMonteCarlo[19]andMD[5,20]simulationsofproteins’behaviorinnanoporeswerereportedbefore.Inparticular,Luetal.[5]andCheungetal.[20]studied

A novel combination of discontinuous molecular dynamics and the Langevin equation, together with an intermediate-resolution model, are used to carry out long (several $\mu$s) simulation and study folding transition and transport of proteins in slit nanopor

foldingofproteinsinsphericalporesofdi erentradii.Cheungetal.studiedthephenomenonasafunctionofthevolumefractionofacrowdingagent,whichtheymodeledbyabedofhardsphereswithrepulsiveinterac-tionwiththeproteins.WhileasphericalporemaybeasuitablemodelforthecavityofGroEl-GroEScomplex,itisnotsofortheporesofmembranes,biocatalysts,andsensorsthatareofprimeinteresttous.Instead,theslit(andcylindrical)poresaremoreappropropriate.More-over,forthetypesofapplicationsthatweconsider,theporespaceconsistsofinterconnectedchannels,whichiscompletelydi erentfromwhatRefs.[5,20]considered.Inaddition,theproteinmodelthatweuse(seebe-low)is,inouropinion,muchmorerealisticthanwhatthepreviousinvestigations[5,20]utilized.Forexample,theyusedasimpli edmodelfortheaminoacidsthatwasbasedontwounitedatom(UA)beads.Moreover,thesidec …… 此处隐藏：16624字，全部文档内容请下载后查看。喜欢就下载吧 ……