五种典型力场对气相中不同末端氨基酸的表现.docx

五种典型力场对气相中不同末端氨基酸的表现.docx

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五种典型力场对气相中不同末端氨基酸的表现

Performancesoffiverepresentativeforcefieldsongaseousaminoacidswithdifferenttermini

XinChen1,ZijingLin1,2*

1HefeiNationalLaboratoryforPhysicalSciencesatMicroscale&CASKeyLaboratoryofStrongly-CoupledQuantumMatterPhysics,UniversityofScienceandTechnologyofChina,Hefei230026,China

2KeyLaboratoryofMaterialsPhysics,InstituteofSolidStatePhysics,ChineseAcademyofSciences,Hefei230031,China

*Correspondingauthor:

ZijingLin;Tel+86-551-63600345;Email:

zjlin@

Abstract:

Thereisagrowinginterestinthestudyofstructuresandpropertiesofbiomoleculesingasphase.Applicationsofforcefieldsarehighlydesirableforthecomputationalefficiencyofthegasphasestudy.Tohelptheselectionofforcefields,theperformancesoffiverepresentativeforcefieldsforgaseousneutral,protonated,deprotonatedandcappedaminoacidsaresystematicallyexaminedandcompared.Thetestedpropertiesincluderelativeconformationalenergies,energydifferencesbetweencisandtransstructures,thenumberandstrengthofpredictedhydrogenbonds,andthequalityoftheoptimizedstructures.TheresultsofBHandHLYP/6-311++G（d,p）areusedasthereferences.GROMOS53A6andENCADSarefoundtoperformpoorlyforgaseousbiomolecules,whiletheperformanceofAMBER99SB,CHARMM27andOPLSAA/Larecomparablewhenapplicable.Consideringthegeneralavailabilityoftheforcefieldparameters,CHARMM27isthemostrecommended,followedbyOPLSAA/L,forthestudyofbiomoleculesingasphase.

Keywords:

Conformation,RelativeEnergies,CorrelationCoefficient,HydrogenBond,MolecularMechanics

1.Introduction

Empiricalmolecularforcefieldsareroutinelyusedintheinvestigationsofstructure-property-activityrelationshipsinbiologicalsystemsasthecomputationalcostoftreatingthesesystemsquantummechanicallyisoftenunbearablyhigh.Theforcefieldsareingeneralderivedbyfittingparameterstodatafromquantumchemicalcalculationsorexperimentsonmodelmoleculesthatmaymimicthepropertiesoftheinterestedbiomolecules.Fittingtheexperimentaldataforthecondensed-phaseenvironmentisemphasized.Thisisreasonableasthestructuresandpropertiesofbiomoleculesinsolutionorcondensed-phaseenvironmentareofthemostinterest.However,thisalsomeansthattheaccuracyoftheforcefieldtopredicttherelevantpropertiesinthegasphaseissacrificed.Italsorepresentsaparadoxinthefittingphilosophyasthequantumchemistryresultsforthegasphaseareindispensiblefortheforcefieldparameterization[1].

Thelimitationofforcefieldsforthegasphasestudyisoftendismissedasirrelevant.Indeed,impressiveprogresseshavebeenmadeinutilizingforcefieldsforthestudyofbiologicalsystems,e.g.,simulatingtheproteindynamics[2-7].However,thecontradictioninherentinthefittingphilosophyhassomeseriousconsequences.Asthereisnorigorouswaytodeterminetheoptimalparameterset,manyforcefieldvariantsareproposedbasedondifferentemphasesofthefittingtargets.AMBER[8],CHARMM[9],ENCAD[10],GROMOS[11]andOPLSAA[12]areexamplesofforcefieldsthatarewidelyinuse.Therehavebeennumerousarticlesandreviewsdiscussingabouttheperformancesofmodernforcefieldsforbiomoleculesinsolutionorcondensed-phaseenvironment[4,5,7,8,13].Thesestudiesshowclearlythataproperchoiceoftheforcefieldisdependentontheresearchsubjectofinterest.

Comparativestudiesoftheforcefieldsarecrucialfortheproperselectionofforcefield,butsystematicstudiesontheperformancecomparisonforobjectsingasphasearerare.Thelimitationofforcefieldsforthegasphasestudyhadbeendismissedasirrelevant.However,thereisagrowinginterestandeffortinstudyingthegaseousbiomoleculesthatarefreefromthecomplicationcausedbythecomplexsolute-solventinteractions[14-20].Consequently,asystematiccomparisonoftheperformancesoftheforcefieldsforbiomoleculesingasphaseisbecomingincreasinglymeaningful.Thecomparisonishelpfulforthechoiceofforcefieldthatisnecessaryformanygasphasestudies,e.g.,MDrunsofbiomoleculewithabout100ormoreatoms.Evenwhentheforcefieldisusedasapre-screeningtool,thecomparativestudyisalsohelpfulforavoidingusingaforcefieldthatprovidesmisguidedinformationaboutthepotentialenergysurface.Moreover,thecomparativestudyisthestartingpointforlearningtheaccuraciesofthestate-of-the-artforcefieldsforthegasphasestudy.Suchinformationisalsohelpfulforknowinghowmuchtheimprovementofforcefieldisrequiredtoprovideresultsforthegasphasestudywithadesirableaccuracy.Theinformationisusefulforguidingthefuturedevelopmentofforcefield.

Thechoiceoftestingobjectsinthisstudyisguidedbysomegeneralconsiderations.First,proteinforcefieldparametersaremainlydeterminedbyfittingdataforcappedalanine,cappedglycineandcappedproline[13,14,21-24].Otheraminoacidresiduesplayonlyminorroleintheparameterdetermination.Theapproachseemstoworkwellforproteinsincondensed-phaseenvironment[2,5,7,14,18],partlyduetothefactthatmostattentionispaidtothebackbonestructures.Forshortpeptides,theinfluenceofthesidechainonthebackboneisexpectedtobesubstantialandhowwelltheforcefieldsworkforotheraminoacidresiduesrequiresdetailedexaminations.Second,theoverallinfluenceoftheaminoandcarboxylterminalgroupsisrelativelysmallforlargemoleculessuchasproteins,butthecorrespondinginfluenceforshortpeptidescanbesignificant.Shortpeptidesareaclassofbiomoleculeswithimportantbiologicalandphysiologicalroles.Theyarealsothestartingpointforthepeptide-baseddrugdesignstudy[25].Theaminoandcarboxylgroupsareimportantintheforcefieldperformancestudy.Third,protontransferiscriticallyimportantfornumerousbiologicalprocesses.Itisthereforehighlymeaningfultoincludetheprotonatedaminogroupanddeprotonatedcarboxylgroupinthetestingobjectset.Therefore,theforcefieldperformancesaretestedhereforalargenumberofgaseousaminoacidswithnatural,protonated,deprotonatedandcappedtermini.

Forcefieldsaremeanttoreproducethestructuralandenergeticinformationobtainedbyexperiments,preferably,orquantumchemistrycalculations.Astheexperimentaldataareverylimited,comparingtheforcefieldswiththequantumchemistrycalculationsaremoreconvenientand,possibly,statisticallymoremeaningful.Infact,thebestonemayhopeforisthattheresultsbyaforcefieldareclosetothatbyquantumchemistrycalculations.Therefore,thequantumchemistryresultsmaybeusedasthereferencestotesttheperformancesofdifferentforcefields.Noticethatthereareanumberofquantumchemistrymethodsandthedensityfunctionaltheory（DFT）basedapproachisfavoredforitsaccuracyandcomputationalefficiency.AmongtheDFTvariantstestedforallneutral,protonatedanddeprotonatedaminoacids,theBHandHLYP/6-311++G（d,p）methodhasbeenshowntoproducethebestenergeticresultsstatistically[26].WhenbenchmarkedwiththeCCSD/6-311++G（d,p）results,thestatisticalqualityoftheBHandHLYPresultsisevenslightlybetterthanthatoftheMP2computations[26].Consequently,theforcefieldsarebenchmarkedwiththeBHandHLYPresults.

2.Method

Theabilitiesoffiveforcefields,AMBER,CHARMM,ENCAD,GROMOSandOPLSAA,tomimicthequantumchemistry,BHandHLYP/6-311++G（d,p）energeticandgeometricresultsaretestedwithfourrepresentativeproperties:

1）relativeconformationalenergies,2）energydifferencesbetweencisandtransstructures,3）numberofpredictedhydrogenbonds（H-bonds）,4）structuralsimilarityasmeasuredbytheroot-mean-square-difference（RMSD）.Thefiveforcefieldshavevariousversionsofparameterizationsandtheirrelativelynewparameterizationsets,AMBER99SB[27],CHARMM27[21],GROMOS53A6[28],ENCADS[29],OPLSAA/L[30],areusedinthetest.

19naturallyoccurringaminoacidsincludingglycine（GlyorG）,alanine（AlaorA）,valine（ValorV）,leucine（LeuorL）,isoleucine（IleorI）,asparagine（AsnorN）,glutamine（GlnorQ）,cysteine（CysorC）,methionine（MetorM）,serine（SerorS）,threonine（ThrorT）,proline（ProorP）,tyrosine（TyrorY）,tryptophan（TrporW）,phenylalanine（PheorF）,histidine（HisorH）,lysine（LysorK）,asparticacid（AsporD）andglutamicacid（GluorE）areconsideredinthetestingsetofthecurrentstudy.Fourterminusformsofaminoacids,natural,protonated,deprotonatedandcapped,areusedinthetesting.Incapedaminoacids,theN-andC-terminiarecappedwiththeacetylandN-methylaminegroups,respectively.Toillustrate,thestructuresofnatural,protonated,deprotonatedandcappedalaninearesketchedinFigure1.

Tobeofhighstatisticalsignificance,theconformationsoftheseaminoacidsareobtainedthoughsystematicsearchesbyconsideringallcombinationsofbondrotationaldegreesoffreedominthetrialstructuregenerations,asdescribedinliteratures[31].TheQMstructuresaredeterminedattheBHandHLYP/6-31G*level.Thenumbersofuniqueconformationsthusobtainedforthesemoleculesareshowninparenthesesasthefollowings.Fornatural,protonated,deprotonatedandcappedaminoacids,theyarerespectivelyAla（8,3,2,6）,Asn（62,9,11,71）,Asp（106,26,24,20）,Cys（78,5,12,49）,Gln（59,8,14,138）,Glu（340,10,16,72）,Gly（16,3,1,4）,His（57,12,8,56）,Ile（85,33,19,62）,Leu（96,12,23,68）,Lys（186,13,51,427）,Met（172,15,31,190）,Phe（31,10,8,32）,Pro（20,6,7,10）,Ser（52,12,19,49）,Thr（71,12,7,52）,Trp