The computational prediction of Raman and ROA spectra of charged histidine tautomers in ...

13 Pages·2016·4.97 MB·English

by  Salvatore Cardamone

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The computational prediction of Raman and ROA
e.
c spectra of charged histidine tautomers in
M. en
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10:30 Aorted Li C20it1e6t,h1i8s,:P2h7y3s7.7Chem.Chem.Phys., aqueous solution
oaded on 3/8/2023 12:ns Attribution 3.0 Unp SHftPuaaaiknsleutcvidtlaioionLtnnoe.araAlieist.ineCPausmoaiknrpbedbyeeairolcimecoohfrmo*ednmapibsoeitcni,naaeblcnsttByfsooetefrtmmhaasAl.nI.uctsmhCacbaroegimnreepos,uftaatbateetnEisoz,wnyaamanlnadmtiocBtadluametnloleincmcghhea,crcnsainsMtmhbaeser,reipaaornofG,dbil.seuLmndidizaffietiiorcctua,akblatesastiotnsadccmaappytaruciarietdybtooyf
ownlmmo conventional techniques. We demonstrate a means for recovering the experimental Raman optical
ber 2016. DCreative Co aeacsxptibveairtinymd(eRanOstsAaig)nndsmpteehcnettorsar.yoWifsehoiifnsttpirdaoirndtieuccuteloaraaimnhopigvoherltadcneocgnerefoienrmocfehraarcsaceculteercarticsioyin.ngTshpcehhyersmeicseaulllttyahnianttsciugonhnatcfmuolbrdqigauunaocnuetistlibyeespt,wasruesecenhs
eptemder a srenparposdhuoctsingfroemxpaermimoelenctaullasrpdeycntraam. iWcsetrsahjeocwtortyhainttothaes‘m‘diaslsleimriclaorintyfo’’rmofatitohnealceonnsfeomrmbelers, swuiittahbinletfhoer
Sn
12 d u resultant ensemble is maximised and representative of the physically relevant regions of molecular
on nse conformational space. In addition, we present a conformer optimisation strategy that significantly
blished e is lice RAcecceepivteedd1192tthhASuegputesmt2b0e1r62,016 roepdtuimceissatitohne sctoramtepguytaytiioenldasl scpoesctstraasosofceiaqtueidvalwenitht qaultaelritnyattiovethoopsteimoisfattihoen asftorarteemgieenst.ioTnheisd caoltnefronramtiveer
e. Puarticl DOI:10.1039/c6cp05744f optimisation strategies. Finally, we demonstrate that microsolvated models of small molecules yield
cls spectra that are comparable in quality to those obtained from ab initio calculations involving a large
ArtiThi www.rsc.org/pccp numberofsolventmolecules.
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pe 1. Introduction more robust analysis of biomolecular structure than more
O
common forms of vibrational spectroscopy because of its
Ramanopticalactivity(ROA)isapowerfulchiropticaltechnique sensitivity to chirality. The ROA signal of a system is largely
that can be used to probe a number of molecular properties. dominatedbythemorerigidandchiralelementsofthatsystem,
In the early days of its inception, ROA was used to deduce and in the case of proteins and peptides this corresponds to
stereochemical information of molecular species by compar- the secondary structure motifs exhibited by the polypeptides.
isonwithbandpatternsofrelatedmolecules.1Unlikeanumber ThismakesROAhighlyusefulforstructuralcharacterisationof
ofotherspectroscopies,ROAintensitiesinthelowwavenumber complex biomolecules, in contrast to Raman spectroscopy,
regionofthespectrumarerichininformation,sincetheseregions where amino acid sidechain signals typically dominate the
correspond to, for example, torsional degrees of freedom2 and spectrum.6ROAisbynomeansconstrainedtopeptidesystems,
largescaleconformationalmodesofmotion.3,4ROAalsopossesses andtheROAsignalsofotherbiochemicalspecies,suchasDNA
thecapacitytodeterminetheproportionsofenantiomerswithina bases7andoligomericnucleicacids,8alsoproveinformative.The
sample,whichisofgreatimportanceinpurificationprocesses.5 utility of ROA in structural analysis has been exemplified over
The structural features of biochemical systems make them the years by a number of studies on the folding,6,9 assembly10
particularly amenable to ROA spectroscopy. ROA offers a far anddynamicalproperties11ofbiochemicalsystems.
Histidine is somewhat unique in its ability to perform a
aManchesterInstituteofBiotechnology(MIB),131PrincessStreet, number of biochemical roles. Traditionally characterised as a
ManchesterM17DN,UK.E-mail:[email protected]; polaraminoacid,histidinedoesnotsubstituteparticularlywell
Tel:[phone] withotheraminoacids.12Thenitrogenatomsoftheimidazole
bSchoolofChemistry,UniversityofManchester,OxfordRoad,
group have long been known to act as proton shuttles, and
ManchesterM139PL,UK
cSchoolofScience,RoyalMelbourneInstituteofTechnology(RMIT), grant functionality for a number of enzymatic mechanisms.
124aLaTrobeStreet,Melbourne,VIC3001,Australia However, histidine has also been shown to participate in
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interactions that are typically perceived to involve large aro- Raman and ROA spectra. We have investigated only the His0
matic amino acids such as tryptophan and phenylalanine. (i.e.bothHis0[NH]andHis0[N H])andHis1+chargestateshere,
t p
Noncovalentinteractionsinvolvinghistidinehavebeenshown since these are the primary forms that histidine takes in the
toexistintheformofstackingbetweenitsimidazoleringanda majorityofbiochemicalsystemsatphysiologicalpH.Theissues
numberofDNAnucleobases.13 of conformer selection, conformer solvation and conformer
Histidine features in the ‘‘catalytic triad’’ of a number of optimisationareeach tackledindependently, andtheireffects
biochemicallyimportantenzymes,suchasserineandcysteine are demonstrated on both tautomeric systems and formally
proteases,whereitactsasaprotonshuttleduringtheprocess chargedsystems.
e. of protein catabolism.14 The Manzetti mechanism15 suggests
c
M. en thatmatrixmetalloproteinases,asetofwell-characterisedcancer
ALic therapeutic targets, attain catalysis through a pair of histidine 2. The problem of conformer
10:30 orted residues that coordinate a Zn2+ ion. The penta-coordinate Zn2+ generation
23 12:0 Unp ihoyndrioslyisnedtuhceedscitsosialectpaepstiaderebvoernsdib.lIendeeleecdt,rorensedaornchorw,iathnidnctahne 2.1 Solvation
wnloaded on 3/8/20mons Attribution 3. pfwioireinotlhFdsp,iievnorsetfuitpecrbishrpi.oo1eta6copasnttiaPadltteyi2os+minsaonshttdiaafstsAesfucoo3ou+-fo,nrdhadniisendtviaidetdiixnenhngeicbeeeixvtiifensontgr:mHhchioissert2mei+d,oienHtxheoiestir1rce+a,spmiHedueuittseai0csl, Tisapnorhmteleevderoiafnlcacettctciiotpuonllntaashsyriasnstmycaslbnautikedoimemcesh,speoitomthmrebtieaciernalceltomvmrseoyolesldoestfeeliismlmnoinslpvdgeeaicnrrpatetatrmitovsibnetoalgdebthemitllhaliaitsenteisgdecp..neIbectSrythigrnoaesctssoeicclbovseetpehnoinectf
om His1(cid:2) and His2(cid:2), where the superscript denotes the formal shown that simply omitting the solvent from spectroscopic
Do
ber 2016. Creative C czfoohrlamergrsei.nTsgthaiitnse.eHffIniesc0atdaodnriditgioiHnniastt1eo(cid:2)stfhcraeonsmeepxthirsoettolionnnaoetinopenaiorsfstatotwfeost,htteahunetioitmrmoiegdreainc- cfsruaolcmchulaeasxtpizoewnriistmteyerinieotln.d1i8scIapnmodoeinreodq,auwcaihdliestny,thdreeesaumlilntosglectwhuialtehtsscaehrveaerergeneledyrgsdepitegiccraieelslssy,
ptemer a atomscontributingtop-delocalisationaroundthefive-membered onlystableifthesolventisincluded,19andoptimisetotheneutral
blished on 12 See is licensed und Nnibtmwiteco,inadrtcbabheozo,enonwldfeesoinrraaimlnwtshgoeae.rydTaebfhlrpkeoeiyimcnlitmgstbihidtdehecacaemzhrobaanloijeniontr,rn,1oait7tgonreraodsnsgioteshnonheanolaelwtadontebtmegoirrnsnebdeaFesriiegano.wfgla1afbtr.yheeFeelfldorenroodimmtcrNoontpgthvheoaenert- tasmiomoelnvTdiensihnueea-tmcrteaew,rnboirmvoeimrdxpoyualnlicjicocmiinrtaegmcanintdotdhdisesepelxesmmpcfilaooiecgdrsinetsiilonltseluovdtdalhveteaaiotsaoinobfanseee.ffhlneWeocccmettitsrhoooigsfnttechanaotebeincofsiountirrisnatmitiodenerictraesa,cl2.el0tcciuottrhlnaiecs-
e. Puarticl are typically varied for conformational studies of histidine in relative to the system in vacuo. The Polarisable Continuum
s Articl This wFihgi.le1;w1(jan,cd)wa2raerethtehecsoindveecnhtiaoinnadlihReadmraalcsh.aTnadurtaonmedriihcefdorramlss, hMaovdeelb2e1e(nPCeMffe)catnivdeCinonpdruecdtiocrt-ilnikgemScorleeecnuilnagrMenoedregli2e2s,(2C3O–2S5MbOut)
s
cce aredenotedbyspecifyingtheprotonatednitrogen, i.e.NpHor lack any atomic-level properties of the solvent, such as the
A NH.Usingthisnomenclature,wecanuniquelylabeltheseven solvent’sabilitytoformhydrogenbondswithasolute.Implicit
n t
Ope microstates of histidine: His2+, His1+, His0[NpH], His0[NtH], solvationmethodshavebeenfoundtoofferminimalbenefitsin
His1(cid:2)[N H], His1(cid:2)[NH] and His2(cid:2). We use the nomenclature computing vibrational frequencies, and therefore vibrational
p t
‘‘microstate’’throughoutthisworkinreferencetooneofthese spectra,relativetogasphasecalculations.26
sevenformsofhistidine. A number of explicit solvation schemes have been investi-
Inthiswork,wepresentanumberofdevelopmentsthatwe gated. At the lowest end, one can include a small number of
haveinstitutedandtestedfortheaccuratecomputationofboth solvent molecules and treat the entire solute–solvent system
quantum mechanically, perhaps embedded in an implicit
solvation field. The number of explicit solvent molecules
treated in this way is arbitrary, and their positioning around
thesolutecanbeproblematic.Solventmoleculescanbeadded
inanadhocfashionaroundpolar(ornon-polarifthesolventis
non-polar)groups,leadingtosignificantimprovementovergas
phase spectra.27 However, a number of problems can also be
attributed to this methodology, such as poor optimisation of
thesystemgeometryowingtoitsdistancefromaminimumon
thepotentialenergysurface.28
AnothermorepopularmethodistheuseofQM/MM,where
the solvent is treated classically and the solute quantum
mechanically. This has proven to be a very successful method
forcalculatingspectra.Forexample,Cheesemanandcoworkers29
Fig.1 Zwitterionic histidine (His0[NH]) where the imidazole nitrogen
t
atoms have been labelled as indicated in the text. The two sidechain have predicted the methyl-b-D-glucose ROA spectrum to an
dihedralangles,w andw ,arealsolabelled. impressive level of accuracy, reproducing the vast majority of
1 2
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spectralfeatures.Morerecently,thisapproachhasbeenfurther We have conducted 100 ns molecular dynamics trajectories
validated on a number of other systems, such as glucuronic forHis0[NH],His0[N H]andHis1+,solvatedinboxescomprising
t p
acid30 and b-D-xylose.31 However, one is still constrained in 469watermolecules,withachlorideionaddedinthelattercase
selectingaconservativenumberofsolventmoleculestoinclude toensurethesystemremainedelectricallyneutral.Throughout,
in the calculation for it to remain tractable; simply including we have used the GROMACS33 molecular dynamics package in
hundredsofsolventmoleculesintheQM/MMcalculationisnot conjunctionwiththeOPLS-AA34forcefield.
routinelyfeasible. Energy minimisation of these systems was initially under-
taken with the steepest descent method, until convergence
e. 2.2 Optimisation of the total system energy was attained. Following energy
c
M. en Complications arise in the QM/MM method of modelling minimisation, we have conducted two separate equilibration
c
10:30 Aorted Li sFoolrvethnet ndourrminagl mthoedegseoomf metroitciaolnoopfttimheissaytsitoenmotfotbheecosyrsretecmtly. pthhearsmeso.sTtahtetfoirmstawinastaain1ansteNmVpTeerqatuuilriebroafti3o0n0,Kus,iwnhgitlhstetBheeresnecdosnend
23 12:0 Unp dmeitneirmmuinmedo,ntthheespyostteenmtiailserneeqrugiyresdurftaocer.elGaexotmoeatrnyoepnteirmgeistaic- wbaarsosatat1tonmsaNinPtTaineqbuoitlhibaratteiomnpeurasitnugretohfe30P0aKrriannedlloa–Rpraehsmsuarne
oaded on 3/8/20ns Attribution 3. mmtniuooanmkleiibcnseugnrleiootstfodienrixiffipothluciescuslilytetsdstootiulffivfdeicinnuedtsltmfwflaooetrlltele-acdnuseslyfeistnsht;eee3md0p,3om1intteihcnnleuitmiidanialcn.elgunTseewivroogenynmosaueftrswhfmaaoctadeelsrl, ouwstfsaaesg0de.c1shtoooMfstPreeenqaautf(io1llirobbnCraagort-)uri.oalonnTmghweebeeirpceleaavcrenttirrdcoiflseivetaadmntiacedssse.hbrAeEWincwuagaatpl-ldosrfofimpndeteeirtslrhytaaocendtqicouoelniolosigb.fyrB1aw0otetahÅds
wnlmo to resolve this problem have therefore been proposed: OptAll by checking the convergence of the temperature for the NVT
Doom and OptSolute. The OptAll scheme optimises the entire equilibrationandthedensityofthesystemfortheNPTequili-
ber 2016. Creative C QissoMluv/seMunatMllmysoyimsletecpmulelem(sweiantnhtedda)ol,epwstsihmriiligesoetrshoeounsOlcpyottSnhoveleurstgeoelnmucteeetthihnordetshfheroeeflidzeeltdshaaonlfl bourarOtieuoqnru.iflBiinboarthaltissohtneopwweaidnsvcaooslnsvuevdmergeaden1tco0e0baefntsesurfrpfoircuoigdehnultcy.ti1o0n0pmso,laencdulsaor
ptemer a the static solvent. The latter method is naturally much quicker dynamics run in the NPT ensemble at a temperature of 300 K
Send than the former, but was found to yield poorer, although still and a pressure of 0.1 MPa. To this end, we have used the
e. Published on 12 article is licensed u icbdwnoeihcfmioetnertpghdmueaatsrnaptittevihaocecetn,crqaaeimluptattoperlirdateocyxvmtpsaepemberetiihlecminttorytedano.iisntSlaootlgsmopyspeebfceoettcrrrtaaerqdlaxue,pqa-eioultciffattilaesibtdtiyedv,tiewwffiblyaeucertcurnoalwtmnaictttposhcauotarrhuisanetccegytarhdtapaendrirendie-- BRtrdieeeoasrrhnueWmslntidwaanasnagelssbnia0innrt.5oht2ese0frtrsaa0m,ct0.two0iTosithtnshaenstaadwcpyeossnnruhaeapomptltresiegdchaaeotlowettmdiigtmheeatosertmsiwheteeeesp.thriCyusaosvooteeuurdoldtoppfemousicrctbroiPeicubvareeradrrsnyiinidmn5eulvtlpahloasn–e-,
ArticlThis tionalcomputationalefforts. precedingparagraph.
s
es 3.3 Filteringofsimilargeometries
c
Ac 3. Technical details
en Forthefollowingdiscussion,the3(cid:3)NmatrixX=[x1...xN]T,N
Op 3.1 Experimentalsetup beingthenumberofatomsinthemolecule,isusedtodenotea
molecular conformation, where x is the Cartesian position
WehavepreparedsamplesofhistidineatapHof7.8and4.2, i
vectoroftheithatom.
bothataconcentrationof0.26M(equivalentto40mgmL(cid:2)1).
Perhaps the most ubiquitous form of geometrical compar-
Spectra were collected over a period of 7 hours, using an
isonbetweentwostructures,XandY,istherootmeansquare
incident wavelength of 532 nm, a laser power of 700 mW and
deviation(RMSD),whichwedenoteRðX;YÞ,
a1.47sexpositiontime.Allspectrahavebeennormalisedsothat
they can be directly compared with the computed spectra. The vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
absoluteamplitudeisthereforeirrelevantinouranalysis. RðX;YÞ¼uutN1 XN jxi(cid:2)yij2 (1)
i¼1
3.2 Moleculardynamics
Thearrangementofsolventmoleculesistypicallyaccomplished However, in the form of eqn (1), a number of pitfalls can be
by use of molecular dynamics. The system is solvated and encounteredwhendealingwithmolecularconformations.The
the resultant trajectory is parsed into a number of snapshot mostsignificantissueisthefactthatRðX;YÞisnotinvariant
configurations. These configurations are subsequently used as withrespecttorigidtransformations. Forexample, if XandY
the conformational ensemble for spectral calculations. Recent possess the same internal geometry, but are rigidly translated
work32 has selected the snapshots entirely randomly, with very relative to one another, then eqn (1) represents the two geo-
rough (qualitative) estimates used to maximise the conforma- metriesasbeingdissimilar.Thesameresultholdsforthecase
tionaldiversityoftheensemble.Thesnapshotsarethenenerge- ofrigidrotationsrelativetooneanother.Ofcourse,molecules
ticallyminimised, andthose snapshotswitha highBoltzmann in homogeneous environments are entirely equivalent after
weightformanensemblethatisconsideredrepresentativeofthe having undergone rigid translations, and so the RMSD in its
dominantsystemconformations. currentincarnationisofnovalueforourpurposes.
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Wecanrendereqn(1)inausefulformbyfindingRðX;YÞ snapshotsintotheensemble,untilanensembleoftherequired
suchthatitisminimisedwithrespecttoallrigidrotationsand size has been constructed. This ensemble then corresponds
translations,i.e.byminimisingthefunction to the set of conformers that are maximally dissimilar from
thetrajectory.
EðX;YÞ¼ 1 XN jUx (cid:2)yj2 (2)
N i¼1 i i 3.4 Abinitiospectrumcalculation
where U is an orthonormal matrix, i.e. U>U ¼I, the identity AllabinitiocalculationswereundertakenusingtheGAUSSIAN0941
softwarepackage,withthetwo-layerONIOMmethod.42Histidine
matrix,andcanthereforebeinterpretedasamatrixdefininga
ce. rigidtransformation.35TakingthesquarerootofEðX;YÞthere- wasmodelledinthehighlayer,andsolventwasmodelledinthe
M. cen fore corresponds to the minimised RMSD (mRMSD) between lowlayer.ThehighlayerwastreatedattheB3LYP/6-31G(d)level
10:30 Aorted Li tthoeetnwsourmeooleucruldaerficnointifoonrmoaftiothnes.mARfMurSthDerissteropbiusstr:eqifuirthede oinfctlhuedoinryg,4T3IaPn3dPpthaeralmowetelarsyefrorwtihthetwhaeteArMmBoElRec9u9lSeBs.fEolreccetrfoinelidc
oaded on 3/8/2023 12:ns Attribution 3.0 Unp crdrroeiooregfttmtlhaheettorbci-monhtiinnoaoiann,rntmaidi.oneeiann.tdlaotsaofrtyrafUsapntnleastamsofnofroeeroðrnm.jtmUsaTautjathiroitoeuoinonsw0n,Þeam,wtbhdteaohaetutearrtnilcexaoqiannuUtnli,rbyreeedawpxorricieeteoshpssmerpaennpnrstouoesdtptnaaecttnseroiudonribnomsbsttyeiapotqtrusfiuoootepetmnhnesaeert. eiaiennmlbeccitFobnhtroeriepotdrionodCrciiaocaantprlgeecttedmuiwmslibaiaaintessnitdaooudtnbisiotaenhnsodgeisf,.s,wqstohuaerneatendhmptaunetomrotlfehomcrmeumiellcoaecrdrwoh-awiolntapeiityrtcheaiacrttlaihoelHenleaasBccmettwrriiovneltsiryotteyanatliuigtacesonsenr.diswtTohefrhomrseer,
wnlmo Theminimisationofeqn(2)withrespecttoU canbeunder- we invoke the analytical two-step formalism, or the n + 1
Doom taken in a number of ways. Historically, the orthonormality algorithm,44inwhichtheharmonicfrequencyandROAtensor
ber 2016. Creative C cpolinedrsitiaonndsfoofrUmahlasvoelubteieonnsadodbetdaintoede,qans(2g)ivaesnLbaygrKanabgescmh,u36l,t3i7- cccaaiellscc,uuwllaaettiihoonnavseoafurtseheedsentphoaerrmaBt3aeLldYciPono/t6ro-d3id1nGiaff(teders)inlaegnvedllehovefalrtshmeooofnrtyihc,ewforhreyiql.euFefoonrr-
ptemer a aisftenramwhedom. WtheeparlogcoereidthminicdeforirvminaglistmhefoforrmsoluotfioUnionfaeqmno(r2e) the frequency-dependent ROA tensors, we have used the
Send B3LYP/rDPS level of theory.45 rDPS is a rarefied basis set that
cle. Published on 12 s article is licensed u wtprhehhceyeescrnieoctmasWlolpyuTuirtnacaentbusdl.ie3t8iVev,3xe9pawrFreeaosyrst,ihtoehelneaWbrfsiooVgarrhkTaUett-¼e,odafUnubdproelvneifttiy-n,eiwageennusvimemcbtpoelrrysopforemf(s3teo)hnreet sDiosinumbnAaainnllsalierendhxlgeycodvibnteraalottshgioiosefennas3ecw-atc2astu1o,v4r+em5a+lceGssynu.4bigc6nthahrstDaihossPefsSa5reue3thsg2wua-cnsilttcmih-bnpesgVweeDsanmpsZies.u-chdstoierffawduntfsooetrmopc-uapflcurchnouvclliaatditroiegonenasr
ArtiThi so-calledcovariancematrix,XYT,andthecomponentsof Xand of the ROA tensors, in keeping with the conventional experi-
s mentalsetup.Wethenobtainedscatteredcircularpolarisation
es Yhavebeencentredontheirrespectivemolecularcentroids.
c backscattered(SCP-180)ROAintensities.Individualconformer
Ac Our final consideration centres on whether U defines a
en proper or improper rotation, as we have previously alluded to. spectrawereBoltzmannweighted,andthosewithaBoltzmann
Op WecanaccountforthisbyspecifyingthatifjXY>jo0,thend=1, weightexceeding0.5%wereusedtoformthespectrum(usinga
Lorentzianbandwidthof10cm(cid:2)1),forcomparisonwithexperi-
otherwised=(cid:2)1,allowingustogivethefinalexpressionforU,
mentalspectra.
2 3
1 0 0
6 7
U ¼W60 1 07V> (4) 4. Conformational ensemble
6 7
4 5
construction
0 0 d
We propose a workflow forthe implementation ofthe Kabsch Past work47 on computing the Raman and ROA spectra of
RMSD for computing a set of maximally dissimilar molecular zwitterionichistidinehasimplementedasimplisticconforma-
conformations, the ‘‘ensemble’’, from a larger set. For our tionalselectiontool.Sixmajorinvacuoconformationalprefer-
work, this larger set corresponds to the MD trajectory, and ences for histidine were proposed to arise from the w ,w
1 2
the ensemble is constructed by parsing snapshots of the MD torsional degrees of freedom: trans-plus (w = 1801, w = 901);
2 1
trajectory into conformers of the ensemble. Throughout, we trans-minus (w = 1801, w = (cid:2)901); gauche-plus–plus (w = 601,
2 1 2
keep the notion of ‘‘trajectory’’ and ‘‘snapshot’’ distinct from w = 901); gauche-plus–minus (w = 601, w = (cid:2)901); gauche-
1 2 1
‘‘ensemble’’and‘‘conformer’’.Tothisend,weproposetheuse minus–plus (w = (cid:2)601, w = 901); and gauche-minus–minus
2 1
of a greedy MaxMin heuristic, where points are added to the (w = (cid:2)601, w = (cid:2)901). These conformers were solvated in an
2 1
ensemble by iteratively transferring from the trajectory those ad hoc manner (a number of water molecules were randomly
snapshots that are most dissimilar to all those currently in addedaroundthehistidineineachcomputationalmodel)and
the ensemble, one at a time.40 So, given some initially large energetically minimised. However, the solvation of in vacuo
trajectory of molecular snapshots, we compute the Kabsch energetic minima does not yield a physically realistic confor-
RMSDbetweenallsnapshotsandtransfermaximallydissimilar mationalensemble.Intramolecularhydrogenbondsstabilisein
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vacuostructures,whicharenotaspreferablewhenthesoluteis intramolecular interactions with the zwitterionic groups are
solvated.Underexplicitsolvation,interactionswithsolventare formed.Intheseregions,solventmoleculesareabletofavour-
more favourable than the intramolecular hydrogen bonds.48 ably interact withboth the zwitterionic groups and the imida-
In addition to this, zwitterionic amino acids are not stable zole,inkeepingwiththefindingsofref.48.Wehavetherefore
in vacuo. This instability necessitates the introduction of non- demonstratedtheinadequacyofusinginvacuominimaforthe
physicalconstraintsonenergeticoptimisationtomaintainthe conformationalsamplingofsolvatedsystems.
zwitterionicform. For the His0 spectra, we have combined both His0[N H]
p
For each system, we have utilised the Kabsch selection and His0[NH] microstate ensembles into a single ensemble.
t
e. methodology outlined in Section 3.3. For each MD trajectory For our microsolvation studies, we have decided to use water
c
M. en comprising20000snapshots,wehaveparsedthe20snapshots clusters comprising 5, 10, 15 and 20 explicit water molecules.
c
ALi whosesolutegeometriesarethemostmutuallydiversebyuseofa To this end, we have selected the closest [5,10,15,20] water
10:30 orted greedyMaxMinheuristic.Solventgeometrieswerenotincluded molecules to the centre of mass of the zwitterionic histidine
23 12:0 Unp icnonthfoermKaabtisocnhafliletenrsienmg.bWleeopbrteasiennetdabcyonthfoisrmKaebrsacnhal‘y‘fsiilsteorfinthg’e’ fromeachconformer.
wnloaded on 3/8/20mons Attribution 3. imDinneepFFrWsliiagg,ezt..ehh22sea.tv(ahwen2adht=ic(cid:2)gcooh6rwl0rieog1,shrkpwt1eeord=nsd,6i4n07t1og)(cid:4)rrt3eehy0ge1ito.hinnCoisovseannccroueetorgnsimoainmnigsnpiotlmehfdeathaHetemai(slwp1l.1+l,Aowcny2oe)andlpyfolsboiryst- 5Ttoh.ethoWeptaimebsiiesgnatchieontoifonfwgseolllva-danteefdidnesdyostmepmintsiimmisanioostnoarittohiueoslnPyEdSi.ffiIcfutltheowPinESg
om shows this fact to result from an unfavourable ammonium– is significantly undulant, conventional minimisation algorithms
Do
ber 2016. Creative C wsimt2aibd=ializs9oe0ls1e,tNhapeHfHavcioos0un[rNtaatbcHtl.e]Cmaominccmreorosntnaiintuegm. tT–hihemeHidpiaosz0oorcleosnaNfmoprpmliinnertgesr,oawfcthitoehnne rsthetrdeuulgocgcelaedl,tatosoplooslewoqgouyreodnfetrtihaselplyaptoioatpelntditmeiarilivseainntiegvregtsyhdseousrnfyaoscttees.mu49ffiOactneeainisndfuremesqcburieebrnintolgyf
ptemer a w1 = (cid:2)601 region for the His0[NtH] microstate arises from increasingly complex levels of theory to obtain convergence of
blished on 12 See is licensed und aiawnnntdeI=irmnHa(cid:4)acpibtso1i1ior8l+tin0tamy.1nIittrcnloeyrgo,cifswoootneanrmttssereasfesaoattr,lhlsotatehwaleslbifigeoplinnrrsoiistfnethiogcminasbnacstlatteearlsdbbe.oviNlexTislyphsilHnaeotsgefeo–isfniacmttmoehinrdepafalocHiztnriomiogslen0ai[.ntNNioptphHnHes] tioothrpdeitsTiemmoralsaiscpsxoiaairmttcniiuoaoumlnmgd,vueeaaruntirvoptaamdnhtiatiavetcevienisfnoogogrffcctetmhooseneactvenohendmroegdrdpegsiunystcpaeaeltra,(eectaviesmemtrwyeyep-escnitocntesanpo.lswlWouyfmohtiuhiinnlteslvgitgon)tekeesoe.demdcio5oe0unt,r5sdy1,
e. Puarticl co1rrespond to an extended imidazole group, where no by commercially available quantum chemistry packages.
cls
ArtiThi
s
s
e
c
c
A
n
e
p
O
Fig.2 Sidechain dihedral values (w and w ) taken by conformers within the three ensembles obtained by a Kabsch filtering of the MD trajectories
1 2
outlined in Section 3.2. His1+ (blue circles), His0[N H] (green diamonds) and His0[NH] (red triangles). Grey hatched regions correspond to those
p t
conformersusedinref.47.
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Whilstonecaninprincipleexplicitlycomputethesecondorder 5.1 Boltzmannweighting
spatial derivatives of the energy at each optimisation step, for
Ifthesoluteisoptimisedinthefieldoftheunoptimisedsolvent,
themajorityofsystemsthisisnotafeasibleapproach.Assuch,
wequerywhetheritisappropriatetousetheenergyoftheentire
theHessianisexplicitlycomputedatthestartofthegeometry
system for Boltzmann weighting the conformation? We make
optimisation, and subsequently updated as a function of the
the(reasonable)assumptionthatthedominantspectralfeatures
displacement of the system from this initial geometry by use
arise from the solute, particularly in the higher wavenumber
of first order derivative information. By approximating the
regions, where librational modes do not feature. Consider the
Hessian at each step of the geometry optimisation, one can
effects of optimising the solute while freezing the solvent: the
e. save a great deal of time. Indeed, such Hessian updating solutewilladoptanenergeticallypreferableconformation,while
c
M. en schemes have proven to be very accurate for a number of the solvent remains unoptimised. The Boltzmann weight of
c
ALi systems.52,53
10:30 orted However,weconsidernowthecasewhereacomplexsystem tphaertiscoulluatrely–suonlvfeanvotusryasbtelemsocloveunldtcboenfroerlmataivteiolyn.loHwowoewvienr,giftothae
23 12:0 Unp bmeigniinmsumin. aGivceonnftohramtatthioenpothteanttiiasl efanrergfryomsurftahcee eisnehriggehtilcy sBoollutztemiasnannwaeicgohmtipsanraottivaelpyrolopwererneeflregcyticoonnofofrtmheatcioonn,trtihbeutlioown
oaded on 3/8/20ns Attribution 3. upcoeponeotddirmuslaiafpsunaprttt,rihootexnhiremffarHaiotlemsiosstnotisahncetooiunnptvihtdeieraagtlHeing.eegsOossnmicaehentiersmays.tehAtehlseneasudroecspqhttui,omitrhieinsedacgtrtieeooaonsmaidnpeogrtporlyyt- osBofollutIthnzteemdlcaioigncnhntaftotweromsefitgehhtrhe’tsiimnssgpaaejtorchgrterufumesmapeteuntcrotte,rsuthwmoeefotohpvfeeraorsapgplolievscseetpnreutccmwtoron.ufmomrmseianencrs.eTtfhhoeer
wnlmo some intermediate approach, where the Hessian is explicitly first takes the energy of the entire solute–solvent system
om calculated, updated for a number of time steps, followed by
Do (‘‘solute–solvent-weighting’’),whilethesecondtakestheenergyof
ptember 2016. er a Creative C etshtxrpeiAkleinicxnipatgllritaececirbtonamraletacpinvouecmteaaptpbiuopetntrawo.taeiTocehnhneoteforfffieotqchpiueeteinmHncceyiyssaiswnniaigdtnhtahiwcsechteuihncreahtnicroyean.semypsateetrtmfeorrhmfaossr jTsuchshetFetrmhoBemeosoltpazTtmraiembaclinesonem1d,pwsawoerleiuegdthsee,twsewitithtohhfaootunthtefoteharnecboosotonhtlhfveoerrnBmitno(el‘tT‘rzssaomblufalretneon-1mw.ewigtehhigethinttgiwn’’)og.
12 Sed und abneednMaulltutedredettaol.i,n30Stewcotiloenve2ls.2o.fInoptthimewisoartikonofwZeireelincosknisiedtearle.d31: schemes, the same six conformers dominate the resultant
blished on e is license OaunnpdotAptltlhimaenilsdaetdOtepsrotSlovopeltunitmte..iNsTeohsteinofgnorltymhatethr,eionpstotihlmuetsieseessintuthdtehieeesn,ftitiehrleedsoyopsfttiemtmhie-, sdwpoeemigcthirntuamonft, tawhlbietehiftirsisontludctoieffn–efsoroerlmnvetenprtr-wiospeiorgorhtuitoginnhgsly,. TtwwhhoeileftiirmsthteecsoBlnoofwolterzmrmewarintinhs
e. Puarticl sationswereperformedonsnapshotsfromMDtrajectories,the snoolurteea-wsoenighttoingsu.sWpeecctanthcaotncthluederetshualtt,iwnotuhlidscnasoet(abnedgweneehraavl)e,
s Articl This sreynstdeemrinisginthiteiaolplytifmarisfarotimonthalelmthienmimouremdeiffinecruglyt.cHonefnocrem,aiftioonne, bbuotththweeiirghctoinntgrisbcuhteiomnesstyoietldhethreessualmtinegdospmeicntrautimngdcioffnefrorrmatehresr,
s
cce isableto‘‘getawaywith’’asimpleroptimisation,thesavingsin significantly. To evaluate whether the resultant spectra are
A computationaltimewillbesubstantial.
n affected by the differing Boltzmann weights, we present the
Ope The reasonable agreement of OptSolute with OptAll in the Raman and ROA spectra generated from the two schemes, in
referencedworksindicatesthatonedoesnotnecessarilyrequire
additiontotheexperimentalspectra,inFig.3and4,respectively.
theentiresystemtobeoptimisedtoobtaininformativespectra.
From the Raman spectra in Fig. 3, there appear to be no
Consideringthesolute–solventsystemasawhole,theOptSolute
pronounced differences between the two weighting schemes.
methodology calculates the spectra of unoptimised systems;
A number of subtle exceptions exist, but certainly none that
technically speaking, it is only a subsystem (in this case the
renderonespectrumsuperiortotheotherwhencomparedwith
solute) that is optimised. This then begs the question of the
theexperimentalspectrum.FromtheROAspectrainFig.4,we
value of energetic minima for these calculations, and whether
see that the two Boltzmann weighting schemes yield spectra
strictgeometryoptimisationisanunnecessaryburden.
thatareagainquitesimilartotheexperimentalspectrum.This
The OptSolute model is appealing owing to the reduced
similaritysuggeststhattheBoltzmannweightingschemedoes
computational complexity of the resultant optimisation. How-
not massively impact on the spectra. However, there are a
ever, its use raises three pertinent questions: (1) How should
the individual conformer spectra be Boltzmann weighted?;
(2) If the OptSolute scheme is valid, can we simplify Table 1 ConformerBoltzmannweightsexceeding1%forthe35micro-
solvatedhistidinesystemsusingthesystem-weightingandsolute-weighting
the calculations further by adopting an even less rigorous
schemes.Thepercentagessumto100%forbothweights
optimisation criterion?; and (3) Are alternative subsystem
optimisation schemes viable? We deal with, and elaborate Conformernumber Solute–solventweight(%) Soluteweight(%)
upon,eachofthesequestionsinturninthefollowingsections.
1 31.6 14.7
As our test case, we take microsolvated zwitterionic histidine 2 22.3 21.6
with five explicit water molecules. The conformers have been 11 6.7 16.3
25 20.1 20.6
takenfromthesnapshotsobtainedwiththemethodologyout-
27 18.0 23.6
linedinSection4. 35 1.3 3.2
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numberofslightdifferencesbetweenthetwo.The1350–1450cm(cid:2)1
regionoftheexperimentalspectrumisdominant,withawell-
defined+ve/(cid:2)ve/+veprofile.Weseethatthefirstpositiveregion
is recovered by both of our calculated spectra, but is arguably
bettermodelledwiththesolute-weighting.
Indeed,itisinterestingtonotethatthisfirstpeakisslightly
blue-shifted relative to the experimental spectrum for the
solute–solvent-weighting, whereas with the solute-weighting,
e. thispeakcoincidesquitewellwiththeexperimentalspectrum.
c
M. en The subsequent (cid:2)ve/+ve profile is present and well-recovered
c
ALi by both, but again the final positive peak is better recovered
10:30 orted withthesolute-weighting.
23 12:0 Unp diffFerroemncethebertewsueletnswtheehatvweogivdeiffn,erweenthaBvoeltczomncalnundedwetihgahttitnhge
oaded on 3/8/20ns Attribution 3. scirmechghopieosrmenonv.eestWmoiseeunssamtelssatohlwle.beIsenolhiletauhvvteeee-atwahbelasliutegndhcectoiednnosgtifdosaecrhidinneemgfitnheoientoilwvy1ei3nsr5oeg0sl–utuo1tle4tt,5hew0eneescrhmmgaia(cid:2)veles1l
wnlmo makesintuitivesenseinthecontextoftheoptimisationschemes,
om aswehavediscussed.
Do
ber 2016. Creative C 5W.2enoLwevaeslsoefssopwthimetihseartiwonecancircumventtheneedtoperform
ptemer a stringentgeometryoptimisationsonoursystem.Wehaveused
Send three levels of optimisation for the comparison: (i) no optimi-
12 d u Fig.3 Raman spectra for the solute–solvent weighting and solute- sation (conformers taken straight from the MD snapshots),
blished on e is license weightingschemes.TheexperimentalRamanspectrumisalsoshown. fd(ioiirs)cptelharece‘4‘mL.5oe(cid:3)onst1er’0’(cid:2)(14M.0aa.ux(cid:3)i.m;1Mu0am(cid:2)x2imfÅo)ru,cmaenrddis2(p.i5ilia)(cid:3)c‘e‘mR10ee(cid:2)gnu3tlara.ru’1’..;8(MM(cid:3)aa1xxii0mm(cid:2)3uuÅmm)
e. Puarticl optimisation schemes available in the GAUSSIAN09 package.
s Articl This Tofheorpetsimulitsaanttiosnp,ec‘t‘Traigahrte’’pr(MesaexnitmeduminFfoigr.c5earnd1.65.A(cid:3)fo1u0r(cid:2)th5 lae.vue.l;
ces Maximumdisplacement6.0(cid:3)10(cid:2)5Å),wasalsoattempted,but
c
A the system proved difficult to converge, and so we have not
n
pe pursuedthislevel.
O
The Raman spectra in Fig. 5 obtained from the completely
unoptimised conformers differ significantly from the other
spectra formed from optimised conformers. This poor
modelling is indicative of the fact that the MD snapshots are
veryfarfromenergeticminima,andsoarenotrepresentativeof
the conformational ensemble of the system. The ultimate
arbiter is the comparison of the calculated spectrum with the
experimental spectrum, and we see that agreement is poor
between the unoptimised and experimental spectra. There
appear to be no features of the experimental spectrum that
arereproducedbytheunoptimisedspectrum.
Turningourattentiontotheoptimisedspectra,weseethatthe
Raman spectra are very similar to one another, and reproduce
a number of the featurespresent in the experimental spectrum.
The series of strong peaks in the 1200–1600 cm(cid:2)1 region are
largelyaccountedforinourcomputedspectra.However,weare
unabletocharacteriseonelevelofoptimisationassuperiorto
theotherfromtheRamanspectra.
TheROAspectragiveninFig.6do,however,differtosome
Fig.4 ROA spectra for the solute–solvent weighting and solute- degree.Surprisingly,thespectralfeaturesinthe800–1000cm(cid:2)1
weightingschemes.TheexperimentalROAspectrumisalsogiven. window appear to be poorly characterised by the regular
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optimisation spectrum, but are relatively strong in the loose
optimisation spectrum. It could be that the amplitude of the
peakatroughly1100cm(cid:2)1dwarfsthesefeaturesintheregular
optimisation.Wenotethatthispeakisnotparticularlystrong
in the experimental spectrum. Assessing the 1350–1450 cm(cid:2)1
region,boththelooseandregularoptimisationschemesrepro-
duce the +ve/(cid:2)ve/+ve signal, with there being no notable
difference between their qualities relative to the experimental
e. spectrum. However, the signal appears to be red-shifted by
M. enc roughly50cm(cid:2)1withthelooseoptimisationrelativetoboththe
c
ALi regularoptimisationandexperimentalspectra.
10:30 orted Basedontheseresults,wehavedeemedthelooseoptimisa-
23 12:0 Unp teixopnertiombeenstaulffiscpieecnttruinmr.eTphroedurecginuglatrhoepstpimecitsraatliofenatouffreesrsoflittthlee
oaded on 3/8/20ns Attribution 3. iolbompeotpdsimreeotivroseipammttiieeomnnntit.saali,Wtnipoeanthrtdeiroceuclaalnatliocrvluteylascttiooenndctsehisdetpheereecxtsptrphaeeercirmterrleaeadlnti-ftvseaehalitftustopirneetgschtaeroureflmosotthsitloeel
wnlmo well-recovered.Consideringtheconvergencelevelisroughlyan
om order of magnitude more stringent for the regular optimisa-
Do
ber 2016. Creative C ttriheoqenu,siirytesssteeremomussghstoolybthehaaolnrfoutuhngenhealycm.eosIsunandrtyeeaoddf,dtiitmthioeentalooloecsffoeomroptputottiemoprietsilamattiiiovsnee
ptemer a totheregularoptimisationforthissystem.Ensuringthesystem
Send isatleastsomewhatclosetoanenergeticminimumappearsto
12 d u Fig.5 Ramanspectrafortheunoptimised,looselyoptimisedandregularly be sufficient for computing spectra. We reiterate that if the
blished on e is license optimisedconformers.TheexperimentalRamanspectrumisalsogiven. stphyoseoterumcnoomipstpifmuartiesfderdosmpMecaDtnrase.nnaeprsgheotitcsmtoinbiem,uomne, aosbtwaienusnedxetrresmtaenldy
e. Puarticl
cls 5.3 Alternativeoptimisationschemes
s Arti Thi Giventhattheoptimisationofasubsystemleadstoinformative
s
ce spectra, the final point we wish to address is whether alter-
c
A nativesubsystemoptimisation schemesyield equallyinforma-
n
pe tivespectra.TheOptAllschemehasbeenfoundtoproducethe
O
highest quality spectra, and so this is the case we use as a
benchmark.However,wecanalsoformulateseveralalternative
subsystemoptimisationschemes:
(a)OptSolute
Thesoluteisoptimisedinthefieldoftheunoptimisedsolvent.
We have already alluded to this approach and its adoption in
previouswork,yieldingspectrathatarecomparabletoOptAll.
(b)OptSolvent
The converse approach to OptSolute, where the solvent is
optimisedinthefieldofthe unoptimisedsolute.Thisapproach
ispotentiallyallthemoreappealing,sincetheoptimisationtakes
placeinthelowlayeroftheQM/MM,andisthereforefaster.
(c)OptSolvent-OptSolute
A‘‘two-step’’subsystemoptimisationscheme–theOptSolvent
methodologyisinvoked,followedbyOptSolute.Byoptimising
thelayersseparately,wehopethatwecanrecreatetheoptimi-
sationresultingfromOptAll.
(d)OptSolute-OptSolvent
TheOptSolutemethodologyisinvoked,followedbyOptSolvent.
Fig.6 ROAspectrafortheunoptimised,looselyoptimisedandregularly We do not imagine this to differ from the previous approach,
optimisedconformers.TheexperimentalROAspectrumisalsogiven. butisincludedforthesakeofcompleteness.
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(e)OptAll does not possess the same relative intensity as that in the
Theentiresystemisoptimisedsimultaneously. experimental spectrum. The best agreement with the experi-
The first two methods, (a) and (b), are concerned with mental spectrum is arguably (c), which appears to recover the
forsaking accuracy for a large decrease in computational cost. vastmajorityofspectralfeaturesfeaturedin(e).
We expect these methods to yield spectra of poorer quality TurningourattentiontotheROAspectraofFig.8,wenotice
than OptAll, but to be far quicker to compute. Contrastingly, thatthe poorperformance of(b) iscontinued, andvirtually no
thelasttwomethods,(c)and(d),looktoreplicatethequalityof experimental features are recovered. We also draw attention to
spectrum obtained by the OptAll scheme, while saving some thepoorperformanceof(d)inthelowwavenumberregions.In
e. levelofcomputationaltimeintheprocess.Inthefollowing,we turn, this poor modelling of the low wavenumber regions
c
M. en willrefertoeachoptimisationschemebytheletterithasbeen obscures the finer details of the high wavenumber regions,
c
ALi listed with in the above enumeration. For example, when andthespectrumasawholedeteriorates.Similarly,(a)appears
10:30 orted referringtoOptAll,wewilluse(e). to be a poor approximation to the experimental spectrum; the
23 12:0 Unp seeFtrhoamt (tbh)epRearmfoarnmssppeactrrtaicpurlaesrleynpteodorinly.FiAgl.l7t,hwreeeimammieddeiaIt–eIlIyI cwoaavresneudmetbaeilrsroefgtihonesspaercetrpuomoralyppmeoadretollebde.pInresceonntt,rbasutt,t(hce) hisigihn
oaded on 3/8/20ns Attribution 3. prHreeooggowiirooelnnyvsserr(ei,1spt6hrn5ee0oseotcntmihtnee(cid:2)dra1,,gfo1raue5ner5dm0otpcehmtniemt(cid:2)iw1insiatatenthnidostn1iht3yes0coe0hfxecpmtmehre(cid:2)eism1l,yoeriweenlsdtpwaelsapcvsteepicvnetecurlatymr)utbhameraert. eeloxxwcpOeewlrfflieamenvreteinnnagutgmasreonbemdemre(eeren)e.xgtpWiolwainitnthsha,tt(ihcbo)eonatehnfxodcrteh(tpehet)ieoasrnrpeeesocauftllrmatasofweoswtbetihafdeiaenavnteeutdiroceabtslht.airnionuteghdhe,
wnlmo are in good agreement with the experimental spectrum. The the optimisation of the solute appears to be the key factor in
om amideI–IIIregionsarewell-recovered,whilethelowwavenumber guaranteeingthequalityofcomputedspectra;thepoorresults
Do
ber 2016. Creative C rmegaiyoqnuseasrteiomnothdeelalemdideequIarlelgyiownesll.oIff(aw)eanarde(tdo),bwehfearsetitdhieoussig,nwael fofrifnotemhre(dase)otaaluniltsdeo(wcf)htpehnreestshupemecsatpbreulcymtdr,ueimrtivaeilssforcoaamlpcuptlehaaetresudn.aosTpoitfirmtehcierseesadotelsvtetahnteet
ptemer a requires some level ofoptimisation, particularly withthe ROA
Send measurements.Hence,thisiswhy(c)significantlyoutperforms
12 d u (a).TheRamanspectraseemtoberobust,ormainlyinvariant,
blished on e is license wofitehIxnprceeogrinamrcdleusnsttiaoolntsh,pweeecletfrveaeelllfoethfaatsutorl(evces).naHtnoodpw(teei)mveoirffs,aewtrieothnhe.avbeefsoturnecdotvhearyt
e. Puarticl thecomputational costassociated with(c)is reducedbymore
s Articl This tthatainonfaolurcfoosldt oanssoavceiartaegderweliathtiv(ea)t,o((ce)).iRselraotuivgehtloy t5h0e%commpoure-
s
ce expensive computationally. Therefore, it seems as if the
c
A OptSolvent - OptSolute or (c) methodology strikes an ideal
n
pe balancebetweenaccuracyandcomputationaltime.Weproceed
O
withthismethodologythroughtheremainderofthiswork.
6. Microsolvation
We define microsolvation to be the explicit solvation of a
system using a small number of water molecules, typically
notextendingbeyondthesecondsolvationshellofthesolute.
The major question we wish to answer is whether computed
spectra from microsolvated systems are able to model experi-
mentalspectra,withouthavingtoresorttoperformingcalcula-
tionsonlargeexplicitlysolvatedsystems.Ifwecananswerthis
querypositively,thenitfacilitatesthecomputationofsolvated
RamanandROAspectra.
6.1 Neutralhistidine
FortheRamanspectrainFig.9,wefindthattheamideIband
at around 1600 cm(cid:2)1 is well recovered by each of the micro-
solvated systems. Since the amide I band is largely indicative
Fig.7 Ramanspectrafor(a)OptSolute,(b)OptSolvent,(c)OptSolvent-
OptSolute, (d) OptSolute - OptSolvent and (e) OptAll schemes. The of peptide CQO stretching modes, it is initially surprising
experimentalRamanspectrumisalsogiven. that its modelling appears to be independent of the level of
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Paper PCCP
e.
c
M. en
c
ALi
10:30 orted
23 12:0 Unp
oaded on 3/8/20ns Attribution 3.
wnlmo
om
Do
ber 2016. Creative C
ptemer a
ed
Sn
12 d u
on nse
blished e is lice
e. Puarticl Fig.8 ROAspectrafor(a)OptSolute,(b)OptSolvent, (c)OptSolvent-
s Articl This OexppteSroimlueten,ta(ldR)OOAptsSpoelcuttreum-isOalpstoSoglivveennt. and (e) OptAll schemes. The Fig.9 RamanspectraforthevariouslevelsofmicrosolvationofHis0.The
s
ce experimentalRamanspectrumisalsoshownforcomparison.
c
A microsolvation, where solvent interactions presumably damp
n
pe the stretching mode. However, upon closer inspection of the
O
microsolvatedconformersusedforthespectra,wefindthatthe We note that we do not manage to definitively recover the clear
peptide CQO is solvated in each conformer, rendering its quadrupletseenintheexperimentalspectrum,althoughtheprofile
modelling independent of the degree of microsolvation. Simi- doesseemtobecomemoreenhancedasweincreasethedegreeof
larly, we recover the amide II triplet at B1450–1550 cm(cid:2)1, microsolvation.Indeed,when20watermoleculesareincluded,we
albeit blue-shifted relative to the experimental spectrum. The areabletodiscernfourclearpeaksintheamideIIIregion.
tripletsignatureappearstobemostprofoundwithasolvation Regarding the impact of the tautomeric forms of histidine,
shellcomprising15watermolecules,wherethecentralpeakis AshikawaandItoh54havefoundthatthebreathingmotionsfor
dominant.Thisresultistobeexpectedsinceasolvationshellof His0[N H] and His0[NH] can be related to Raman peaks at
p t
15 water molecules appears to coincide with the number of 1304/1260 cm(cid:2)1, respectively. In the same work, two additional
watermoleculescomprisingthefirstsolvationshellforzwitter- markerregionscharacterisingimidazolestretchingmodesbetween
ionic histidine. Since the amide II region is representative of thetautomericformsofhistidinewereproposed:1568/1585cm(cid:2)1
peptide N–H bending and C–H stretching modes, we expect and1090/1105cm(cid:2)1.LaterworkbyToyamaetal.55hassuggested
thisregiontobehighlydependentonsolventinteractions.Itis, an additional marker region at 1320/1354 cm(cid:2)1. Unfortunately,
nevertheless, surprising that the quality of our computed the majority of these marker regions inhabit the strong amide
spectradeteriorateswith20watermolecules. regionsoftheRamanspectrum,makingthemdifficulttodiscern.
The amide III region is slightly less well-modelled by our However, the 1090/1105 cm(cid:2)1 region occupies a low intensity
microsolvatedsystems.Intheexperimentalspectrum,weobserve regionoftheRamanspectrum,andappearstobecharacterisedin
a well-defined quadruplet of peaks, spanning 1200–1350 cm(cid:2)1. bothourexperimentalandcomputedspectra,ateachmicrosolva-
This region is dominated by C–N stretching and N–H tionlevelexcludingthespectrumwith5waters.
bending modes, and we would expect this region to be as The experimental ROA spectrum is not quite as well-
solvation-dependent as the other two regions we have discussed. recovered as themicrosolvated spectra, asdepicted inFig.10.
27386 | Phys.Chem.Chem.Phys.,2016,18,27377--27389 Thisjournalis©theOwnerSocieties2016