electrostatics in biochemistry

Environmental Health Perspectives Vol. 61,pp. 191-202, 1985 byPeter Politzer,* Patricia R.Laurence,*t and Keerthi ivatJayasuriya’ The electrostatic potential ¥/7) that iscreated inthespace around amolecule byitsnuclei and electrons (Created asstatic distributions ofcharge) isa very useful property foranalyzing and predicting molecularreactivebehavior.[Lisrigorouslydefinedandcanbedetermined experimentally aswellascomputationally‘The potential has been particularly useful asanindicator ofthesites orregions ofamolecule towhich anapproaching electrophile isinitially attracted, and ithasalso been applied successfully tothestudy ‘ofinteractions that Involve acertain optimum relative orientation ofthe reactants, such asbetween a‘ruganditscellularreceptor.Avarietyofmethodsforcalculating V7)isavailable,atdifferentlevelsofrigor. For large biologieally active molecules, multipole expansions and superposition ofpotentials com- puted forsubunits have been found tobeeffective. Alarge number ofchemical and biochemical systems find processes have now heen studied interms ofelectrostatic potentials, Three examples ofsuch applictationsaresurveyedinthispaper.Thesedealwith:(a)reactivepropertiesofnucleiacids,includingtheftcomponent bases; (b)biological recognition processes, including drug-receptors and enzyime-substrate Interactions; and (c)chemical carcinogenesis, referring specifically tothepolycyclic aromatic hydrocar- bons and halogenated olefinsandtheirepoxides.Foeachoftheseareas,examplesoftheuseofelectrostatic potentials inelucidating structure-aetiity paiterns are given. The Meaning and Use ofthe amolecule should therefore helpconsiderably ininter-preting itsreactive behavior toward charged species ElectrostaticPotential (even, qualitatively, whentheyarelarger thanpoint charges) andinpredicting thesites ofthemolecule at iti signi which they aremost likely toreact. Indeed, over theDefinition andSignificance past15years,theelectrical potential hasbecomeawell, Anydistribution ofelectrical charge, suchasthe elec- established toolfortheelucidation ofmolecular reactive trons andnuclei ofamolecule, creates anelectrical po- properties (1-4). Inthese applications, thesystem is tential V(7*) inthesurrounding space. V(7*) maybe normally viewed ashaving astatic distribution ofelec-regarded asthepotential ofthemolecule forinteracting tronicchargearoundarigidnuclearframework; hencewithanelectrical charge locatedatthepoint7.Fortheterm“electrostatic potential”iscommonlyusedfor example,anapproaching pointwillcharge=Qwillin-VF). teract withthiselectrical potential, withanenergy of _Ifamoleculehasanelectronicdensityfunction(7), interactionequaltoexactly+QV(7),where?isthethenitselectrostatic potentialatanypointisgiven positionofthepointcharge.Thusapositivepointchargerigorously byeq.()): isattracted tothose regions inwhich V(7) isnegative, since this leads toanegative (stabilizing) interaction energy, anditisrepelled from regions ofpositive po-tential,inwhichtheinteraction energyispositiveand ~ Z. adestabilizing. vm)=YA -fore aAknowledge oftheelectrical potential, V(7"),around [Ra-F] [FF “Department ofChemistry, University ofNewOrleans, NewOr-Zaisthecharge onthenucleus A,located atR,.TheTeane oraas,DEMS UniversityofNewOrleans,NewOr;Gee"sermontherightsideofeq.(1)represents the {resentadrs: LyinUCL, 64NewaanSteetLandonWIA contribution ofthenlei,whichispositive; thesecond 19 POLITZER ETAL. term brings intheeffect oftheelectrons, which is tions give relatively good results (first-order accuracy)negative. forproperties thatarecalculated fromtheelectronicEq.(1)isanexact formula fortheelectrostatic po- density function, asisV(#) (6-7). Furthermore, ex- tential due tothesetofnuclei {Z.4} and theelectronic tensive investigations have shown that agenerally re- density p(7). Ontheother hand, thelatter function is liable electrostatic potential eanbeobtained even with generally obtained from anabinitio orsemiempirical __self-consistent-field (SCF) wave functions that arenotmolecular wavefunctionandisaccordingly approxi- nearHartree-Fock quality(J,8-13).V7)isalsobeingmate, asisalso, therefore, theresulting V7), Ithas determined experimentally toanincreasing extent, by been'shown, however, that Hartree-Fock wave fune- diffraction methods (14~17), butatpresentthequantum chemical approach remains themore accurate andmore - ractical one. ob ~>"Figure 1showsourcalculated electrostatic potential 63-~jN foraniline,computedfromtheabinitioSCFSTO-6G4 wave function using anoptimized geometry. Thevaluesa(@SZe) ofthecontoursaregiveninenergyunits(keal/mole)and(ps) NF(Meactuallyrepresentthequantity+QV(7),whereQ= ooNKSY©)@)| KeWitrisis ofcourse,equal,inmagnitude andsignto ~GantKe)\SS\\_¥/7').1 Thus,therearetheinteractionenergiesofthe oat]@)©)Guai)Dstaticchargedistributionofanilinewithaprotonlocated aaN AZ anywhere initsneighborhood. InthoseregionswhereA)Ke\@)(==V(7")isnegative,theeffectoftheelectronspredomi-<?ZS)VKnates(Eq.(1)],andtheseareaccordinglyattractiveto aaWF ))anapproachingelectrophile.Asanticipated,thepoten-\SING tialisstronglynegativeaboveandbelowthearomaticE/ 4) ringinaniline,reflectingthepresenceofthemelectrons, WY ‘The most negative value, -87.2 keal/mole, isinthere- - gion that isassociated with thenitrogen lone pair, and isindicative ofthe basic nature ofthe amine group. - Animportant featureoftheelectrostatic potential is a that itisarealphysical property, asevidenced bythe “ on fact that iteanbedetermined experimentally (14~18).a 6a . Itissigoroulyandunambiguously definedbyEa., :on andhasaclearphysical meaning: itexpresses thene coe7 .electrical effectoftheelectrons andnucleiofasystem Loy ata tS inthesurrounding space. Thephysical reality ofthe aera s__ electrostatie potential stands incontrast totheunavoid- Bot BN ~ee an ablearbitrariness andambiguity associated with manyVo ome other indices ofreactivity, suchasatomic charges [which ay - <=< areactually apoint-charge model representation ofSy NY “=< V(7)]. While thesehavesometimes beenquiteuseful iSf (DM)(©)Z(oOWe)ininterpreting generaltrendsandrelativetendencies, 0-77 ASSAY) theyarenevertheless defined properties anddonotdi-Sa SZE rectly correspond toanything real.Thus, theymayNeOa “BSS 5sometimes havelittleornophysicalmeaning(19-22), \63joh AnExample:Cytosineve Thepointsthathavebeenbroughtoutinthepreced- Nn‘ ingdiscussioncanbeillustratedbyreferringtothecal- ae NN culatedelectrostatic potentialofeytosine,I(28).This shows alarge negative region inthemolecular plane, stentiaofaniine. Eleetrotaie encompassing bothN,andO,.Withinthisregionthere areatalSfcelineoecenahaecnnutsSeonGsG avetwolocalminimainV7");theseavepointsatwhich Mravefiction using ageometry thathasbeenoptimized atthe V(7F) attains itsmost negative values, andtowhich an 'ST0-3G levelwiththe GAUSSIAN 80program (179) (A)inthe _eleetrophile would therefore bemost strongly attracted. plan ofthe ring;(B)inthe symmetry planeperpendicular tothe Oneofthese isnear Nz,where thepotential reaches aPeeelmine,AcOONaceCaledSekiBrake. Valueof-93.5keal/mole, andtheotherisnearO,,where‘87.2kealimole andB=-10.2kcal/mole. Thepositive region inthe V(F) =—86.7 keal/mole. There isalsoamuch weaker Tower leportionof(B)isduetotheaminehydrogens. regionofnegative potential aboveandbelowthemo- MOLECULAR ELECTROSTATIC POTENTIALS 193 aguide tomolecular reactivity. ; Because ofthese limitations, the electrostatie poten- RUN tialismost useful asaguide totheearly stages ofaNj reaction, inwhich theattacking species isnotyetvery{ closetothemolecule Mandtheirmutual polarization, Pare charge transfer, ete.,arerelatively insignificant. TheNy5 implications ofthiswillbecomemoreapparentinasub- ZL \ i sequent section,0 Itshould alsobepointed outthattheelectrostatic8 i potential cannot beapplied asreadily totheanalysis of x nucleophilic processes astheelectrophilic ones.A.pos- itivepotentialdoesnotnecessarily indicateacorre- it it ji ait The lecularpla 13.7keall »spondingtendencytoreactwithnucleophiles. aminenitrogen,MannaOF-18.7Kealmelebythetivechargesofatomnucle,beingveryhighlycon- Fromtheelectrostatic potential, itwouldbepre-eentrated, createstrongpositivepotentials thatmay dictedthatanelectrophile wouldpreferentially attackoutweighthenegativecontributions oftheelectrons,cytosineinthemolecular planeandattheN,position; Whicharelispersedibytoenacelessmaynetreflect itssecond choice would beOs.Thisisexactly whatis@Corresponding ‘y pl.Wwe-observed expe yfavor centlydeveloped aprocedure thatdoesmakeitpossible cperimentally. Nyisthegreatly favored site e forbothprotonation andalkylation(whichisbelieved ‘iapplySeton poventialstotheStudyofthere siick) (24-27 licreactions sapproack cytosineanteToCathyahahNEoeeeVCP)forthesubstratemoleculeinastateofdistorted nificantsecondary interaction between O,andtheCull) eometry, alreadysomewhat amenable totheattackof (27,28). When Njisnotaccessible, asinDNA (inwhich thenucleophile. itisinvolved inhydrogen bonding), some electrophiles havebeenobserved togoinstead to0,(29),whileothers Relationship between Electrostaticthen simply donotreact with thecytosine (26). Thus, 4 wae es,cytosine, chosenhereasanexample, isobserved ex-Potentials andKinetic/Mechanisticperimentally tobehave toward electrophiles inexactly Aspects ofReactions themanner thatwouldbepredicted fromitseleetro- 1aystatedearlierthattheenergyofinteractionstprolicuionsbaseduponthecalculatedatomiecharges, betweenapointcharge=locatedaFantheelec,ontheotherhand,wouldbeseriously inerroriney. trostatic potential V(-F)created bysomecharge distosine, themostnegative atomic charges arefoundto‘ibution isgivenexactly by+QV(7"). Ifonewishes to beonN,and N,,~0,72and -0.60, respectively, followed ®¢c0unt forthefactthatthecharge distribution willbebyO,,~0.52, andfinally N,,-0.46 (30).Thisistotally affected (polarized) insome manner bythepresence ofinconsistent withtheexperimental factthatN,isthe thepointcharge, thenperturbation theory canbeused most attractive siteforelectrophilic attack,withO,being‘0obtaintheinteraction energy;=QV(7)willbethe next(24-29), ” * first-order term intheresulting expression (3,31). For+29) interactions between twocharge distributions (asop- Ce . posed toacharge distribution andapoint charge), theLimitations upon theUseofthe mathematical treatment becomes morecomplicated, but Electrostatic Potential theelectrostatic contribution remainsawell-defined ele- a. ‘mentoftheinteraction energy. Forthese reasons, V7) ‘Whiletheelectrostatic potential hasproventobeanhassometimes beenregarded asrelated tothether- effectivetechnique foranalyzing andpredicting molec- modyamic, ratherthankineticandmechanistic, as- ularreactive behavior, itisimportant torecognize cer-Hersofreactions fainintrinsiclimitations uponitsuse.V7),asdefined "Tnreality,however, theapplications oftheelectro- byEq(D,is.aproperty ofamolecule Minsomepar statiepotential cutacross thetraditional division be-ticular state;itreflects onlythecharge distribution oftween thermodynamic effects ontheonehandaedMinthatstate.(7)doesnottakeintoaccount the jinetie/mechanistie onesontheother.Oneaspectofitschanges thatoccurinMasitbeginstointeract with relationship tothelattereanbebrought outintermsfameapproaching species (e-g.,polarization andcharge oftheBell-Evans-Polanyi principle (34-36). Accordingfransfer), nordoesitreflect inanywaythenature oftothis,inthereactions ofaseriesofrelatedmolecules, thelatter. Onecanofcourseusevariousapproaches, 4,a,”A.withsomegivenreactantB,thediffer. includingperturbation techniques, toestimate thecon- encesintheactivation energies arelinearly related to tributionsofsuchfactors, andsomesignificant progress thedifferences intheheatsofreaction. Thisisadirect hasbeenmadealongtheselines(3,31).However, this= . oesbeyond theuseofelectrostatic potential itselfas“Forexample,theelectrostatic potentialofafreatomispostive 194 POLITZER ETAL. link between thermodynamies and kineties. Itmeans per. The preceding discussion shows, however, that that iftheelectrostatic potentials atsome particular when theelectrostatic potential isbeing used toeluci- sites insuch aseries ofmolecules arerelated totheir date electrophilic andnucleophilic processes, itisclearly interaction energies with B,then they arealsoamea- related tothekinetic andmechanistic aspects ofthe sure oftherelative activation energies andhence rel- reactions. ative rates ofreaction ofthese molecules with B. Theelectrostatic potential ofamoleeule isindicative Methods ofCalculating the ofwhat anapproaching species encounters when itfirst acomes intotheneighborhood ofthemolecule, before Electrostatic Potential significant polarization ofthelatterhastakenpleae.The Theelectrostatic potential ofachemical system ispotential isaccordingly relevant tothequestion ofwhat given rigorously interms oftheelectronic charge den- isthemost favored pathofapproach andthepreferred sity,p(7*),byEq.(1).Inpractice,molecularelectronic region ofinitial attack. Inthismanner itreveals me- density functions obtained byquantum chemical meth- chanistic aspects ofareaction. Forinstance, theelec- odsareessentially always approximations, atvarious trostatic potential computed foracehepthylene (II)shows_possible levelsofaccuracy. Starting withsuchap(7),pe onecanthen proceed toevaluate Eq.(1)either rigor- ouslyorapproximately. Evenwhenthisisdonerigor- 10) ously, however, theaccuracy oftheresulting V(7) is "naturally limited bythat ofp(7). Hog “ Various procedures forcalculating V(7) have been discussed andanalyzed elsewhere (3,43). Here weshall avy 4% limitourselves primarily tomentioning afewrecent.developments. thattheC,—C,regionhasthemostnegativepotential _,V(7*)canofcoursebeobtainedbysubstituting (7)associated withitandtherefore shouldbethemostlikely¢irectlyintoEq.(1)andevaluating—exaetly orap- targetforelectrophilic attack(37).Thisisinfullaccord _Proximately—the resulting integrals, oralternately, by withtheexperimental observation thatprotonation in- integrating another exactrelationship, Poisson's equa-itially occurs exclusively atC,orCz,even though the Hon44,45): ‘moststable finalsitefortheproton isnearC,,towhich VV) =4ap(F) @iteventually migrates (87,38). [From the calculated atomic charges (37),protonation would incorrectly be Another approach thathasbeenstudied veryexten- predicted tooccur atC,orC,.]Thustheelectrostatic sively involves expressing V(7") asamultipole expan-potential correctly revealsakeymechanistic featureofsion,writtenintermsofoneormorecenters(46-48).thereactivity ofthismolecule, thesiteofinitial proton Jngrecent adaptation ofthistechnique, designed toattack; thisisnot,however, thesitethatisfavored facilitate thetreatment oflargebiological molecules, thermodynamically.. <nvat) eachoverlap termintheelectronic density function was Asecond suchexample isethylene, forwhich V7) Teclaved byaonte-conter expansion thatwentasfarasshows themostfavored pathofapproach ofanelectro-{)2 auadrapole terme (4d),Thismethod wasfound tophiletobeperpendicular tothemolecularplaneatthe—Sorneutiyreproduce VC#)atdistancespreaterthan2.0midpointoftheC=Cbond(9).Thisisin fullagreement 4fromtheconstituent atomsofthemolecule. Inlater withtheexperimental evidence fortheaddition reae- provements ofthisapproach, multipole expansions tionsofCl,,Br,andT,,according towhich theseoccur Wereusedtorepresent localized molecular orbitals (50),through anintermediate halonium ion,ITT(40): andoctopole terms wereincluded intheexpansions (51). + Bychoosing thecentroids ofthe localized molecular or- x bitalsasthecenters fortheexpansions, thedipole terms iwwonton, could beeliminated.MeMe Theseexpansion procedures havebeenusedwithinthe context ofascheme inwhich V(7) foralarge bi- The halogen, X,subsequently moves tooneofthecar- ological system, such asasegment ofDNA, isobtained bons. Another case inwhich theelectrostatic potential bydividing itinto subunits, computing wave functions, correctly predicts that theinitial approach istoabond electronic densities and electrostatie potentials forthe rather than anatom isthat ofcyclopropane, inwhich individual subunits, and then superposing these poten- the most negative regions are associated with the tials toproduce V(7") forthewhole system (52,53). The strained C—C single bonds (41,42). subunits arecreated bybreaking appropriate single Ontheother hand, theinitial siteofattack does very bonds andintroducing hydrogen atoms tosaturate the often correspond tothemost stable product. Many such resulting free valencies. Tests ofthis approach indicate examples have been presented and reviewed (1-5), and that ifthesubunits arechosen carefully, theresulting one(cytosine) was analyzed indetail earlier inthis pa- superposed potential should beagood approximation to MOLECULAR ELECTROSTATIC POTENTIALS 15. ‘that computed directly fortheentire system (51,52); —_trostatic potentials hasgreat appeal, even apart from theperturbing effectsoftheaddedhydrogens arerel-_anyrelation togrouppotentials, because ofitssimplic-atively insignificant. ity,andithasaccordingly been thesubject ofconsid- Multipole expansions arecustomarily expressed in erable investigation. Avery good representation ofVF) terms ofspherical polar coordinates referred tothevar- eanindeed beobtained inthismanner, butitwillnor- iouscenters. Inavariation ofthis, expansions written mally require alarge number ofpoint charges situatedintermsofspheroidal coordinates wereusedwithsome throughout thespaceofthemolecule, usuallynotlimitedsuccess toobtain analytical expressions that approxi- tojust thepositions ofthenuclei, (Analternative isto mate V(T>) forseveral molecules that canberegarded relax thisrequirement buttousethepointchargemodel asbeing oblate-spheroidal inshape (54,55). only forthecontributions ofremote portions ofthesys- The concept ofrepresenting localized molecular or- tem.) More extensive discussions ofthepoint-charge bitals bymultipole expansions hasthedesirable feature approach aregiven intheliterature (3,43,60-64). that such expansions could conceivably betransferred fromonemolecule toanother, provided ofcoursethat ' thelocalized molecular orbital isreasonably valid for i logicalbothmolecules, Thepossible transerabiity ofsuchSOME Applications toBiolog!“group potentials,” representing, forexample, lonepairs, Systems core orbitals, ¢or7bonds between thegiven pairs of | | . .atoms, ete.,hasreceived aconsiderable amount ofstudy Electrostatic potentials havebeenwidely usedin(1,2,56),withsomeimpressive andencouraging results. studyingvariousbiological systemsandprocesses. SomeA'great deal ofcomputational time could besaved ifaimportantdevelopments inthreesuchareas—nucleic satisfactory approximation toamolecular electrostatic acidreactive properties, biological recognition, andpotential couldbeachieved bycombining theappropri- chemical eareinogenesis—shall besummarized inthisategrouppotentials, transferred fromothersystems. _section.‘This would alsomake itpossible toobtain atleast qual- itative representations ofV(7") forvery large systems i " eic Acidsthatcanrotpresently beUvatedhyothermeans,This Reactive Properties ofNucle "isalreadybeingdonetosomeextent(57). Theelectrostatic potential hasbeenappliedexten-Onemeansofexpressing grouppotentialsisinterms_sivelytotheinvestigation ofthereactivebehaviorof ofappropriately chosen anddistributed pointcharges. boththenucleic acidbasesandalsoofincreasingly largeThisapproach hasbeentested foranumber ofmole- fragments oftheDNAandRNAhelices themselves.cules, withoverall satisfactory results (58,59). Itwas Forallofthebases [adenine (IV), guanine (V),cy-suggested thatsuchpoint-charge group potentials might _tosine (1),thymine (V1), anduracil (VID), themostbeparticularly useful inrepresenting theeffects ofpor- negative values ofV7)(thepotential minima) arefound tions ofamoleculethatarerelativelyfarfromtheregion_inthemolecularplaneandareassociatedwiththenic ofinterest (58). trogen atoms oftherings andthecarbonyl oxygens Theuseofpointcharges toestimate molecular elec- (28,65). These dataaresummarized inTable 1.Adenine ae " i i*6x EN, Hay oN6™ wy 8Scy, 8 cses ¥ PoP Seen wl ony ynDy omyih i 9 ° i] i} tyecechy Bayhn cis \ i vin t ! 0a OH oFny Somi‘ 14 196, POLITZER ETAL. Table1.Caleulated electrostatic potentialminimaofnucleic ies(68),inwhichvariouscolorsareusedtorepresentacidbases.” specific numerical ranges ofV(7). The three-dimen- SE sional effect isachieved byvarying thesizeanddensityoleae Lacationofminimum Vankealimole Sfthepointsonthefigures,Cytoine NearNinmolar lane 85) There hasbeenadetailed investigation, usingthe3Seae icarer csenea pte Adenine (IV) Near N;,inmolecular plane =n. tials change intheprogression from isolated nucleic acid Near Nj,inmolecular plane =a. bases tonucleosides, nucleotides, single helices andfi-NearNoinmolecularlane oe nallydoublehelices(onedoublehelicalturn)(65,69,70). a ly(guanine-eytosine) andpoly(adenine: thymine) modelGuanine(V)NearNj,inmolecularplane -31 sequences wereusedinconstructing thehelices.Ingen-Near Og.inmolecular plane =. eral, itwasfound that thepotential minima associated‘NearNs,inmolecular plane ~H. withthebasesbecome veryconsiderably morenegative ‘Tymine (V1) NearOyinmolecular plane -—=«-g@,5.-«=S« ogessing through thissequence. Forexample, Vinin NearOs,inmolecular plane cSt forN;ofguanine goes from ~88kcal/mole inguanine itselfto-683kcal/mole inthepoly(guanine-cytosine) Urncil(VII) NearO,,inmolecular plane 813 model ofB-DNA. Amajor portion ofthese changes is —____Near02,inmolecularplane__-54._—_ quetothestronglynegativecontributions ofthephos- “DaatakenfromBonaccorsietal.(2)andPulimanandPullman phates.Therelativeorderingofthepotentialminima (65). ofthebases isnotpreserved asthecomplexity ofthe system increases. hasthree minima; twoofthem, near N,andNg,are _Theconclusion thatthepotential minima associated similar inshape anddepth, while thethird, byN,,is With thereactive centers inthebases become more narrower andshallower. Guanine alsohasaminimum Negative asthelatter areincorporated intolarger sys- near Na,butitsdeepest oneisinthevicinity ofN;and tems isconsistent with theobservation ofaparallel ispart ofthenegative region thatincludes asecond increase inreactivity toward chemical carcinogensminimum closeto0,.Cytosine, already mentioned, has(70,71), (whicharebelieved tobe,generally, electro-asimilar extended region ofnegative potential, with _Philic innature). Thisisindicative oftheimportance ofminimanearN,andOs,whilethymineanduracilhave__theelectrostatic factorinthesecarcinogenic interactions,minimaassociated withthecarbonyl oxygens. Aspartofthisveryextensive studyofthepropertiesTntheremainingregionsinthemolecularplanes,V7)_ofthenucleicacids,electrostatic potentialshavebeen ispositive forthesemolecules. However therearesome_calculated forseveralformsofDNA(A-,B-,alternatingrelatively weak out-of-plane negative regions andmin- _B-,C-,D-andZ-DNA) aswellastRNA" (65,66,69-ima;thestrongest oftheseareaboveandbelowthe_78).Thedistributions ofnegative potential inthevar-amine groups ofadenine andcytosine, with others near ioussystems andtheir reactive behavior, toward pos- C,ofguanine andthe C=Cdouble bond ofeytosine. itive ions forexample, areanalyzed indetail. Further Inproceeding tolarger systems, there arises the references tothese studies willbemade inthediscus- question ofhow topresent V(7) inaform that canbe sion ofchemical carcinogenesis. readily understood and interpreted. The usual proce- dure ofplotting two-dimensional isopotential contour pio jowi ition Pimapsissuitable forarelatively smallorplanar mole- Biological Recognition Processes cule, orwhen certain planes ofobvious importance canbeidentified, whichcontaintheinteresting features, _,,D™4&Teveptor andenzyme”substrateinteractions are Forlargesystems, aneffectiveapproach istousethe{hvinitialttenisoneof“rocoenition": the receptorofconceptofamolecular surface(66,67).Thisisgenerally theinitialstepisoneof“recognition”; thereceptor 0}(oho tebete ally theenzyme “recognizes” thatanapproaching molecule0 eoutersurface ofasetofintersecting hirtainkeyfeatures thatwillpromote theirmutualspherescentered ontheindividual atoms,withradii(#5certain‘Sxshrecognitioniskelievedtotakepl given byxiv,where RyisthevanderWaals radius of mteraction. Suchrecognition isbelieve eetheatomandxis’Variable paremeter thathasthe ‘YBealywhenthedrugandthereeeptor,ortheenzyme samevalueforalltheatoms.BychangingthemagnitudepreciostheformationTancaerbet ofx,oneeanobtain asetofsurfaces thatareatvarious "Since theelectrostatic potential ofamolecule is@distances fromthenuclear framework, Thus,aproper phvsically-meaningful representation ofhowitisper-choiceofxwillensurethatthesurfaceissufficiently farSee eeeeeeneeeiti Itejook fromeachnucleus thatasatisfactory representation of FT ata eeeVCP)canbeachievedbtheapproximate pre. ‘2.thepotentialinseekingthekeyfeaturesthatdeter-canbeachieved byoneoftheapproximate pro-ninewhetherornotaparticular recognition willoccur.cedures mentioned above. Theelectrostatic potential hasindeed proven tobeanOneeffectivemodeofPresenting thelectrostatie iereffectivemeansofanalyzingandelucidating recognitiontentialcalculated oteathree-dimensiot 4finlect processes; infactthisisoneoftheareasinwhichithas surface isbymeansofcomputer-generated colorgraph- eenusedwithgreatestsuccess.Inanumberofin- MOLECULAR ELECTROSTATIC POTENTIALS a stances, theextent towhichacertain drugorsubstrate experimentally, itsaffinity fortheLSD/5-HT receptorreacts with aparticular receptor orenzyme hasbeen wasfound tobelower byafactor of10than thatofshowntoberelatedtothedegreetowhichtheelectro- _eitherLSDor5-HT,butcomparable tothatoftryp-statiepotential oftheformerpossesses certainchar-_tamine(whichhasnohydroxyl group).acteristics that have been identified asbeing required __Aninteresting observationthatwasmadeinthecourse forinteraction with that receptor orenzyme. Several ofthis study was that when V(7*) was calculated for suchstudies willbebriefly summarized. LSDbymeans ofthepoint charge approximation, using 5-Hydroxytryptamine, (VII (5-HT, alsoknown as atomic charges centered onthenuclei, itfailed tore~ serotonin), isaneurotransmitter thatinteracts withre- produce thecrucial potential minimum near theCy.=Cy double bond (76).Thus thepoint-charge approach could nothaveledtotheexplanation thathasbeengivento ; aecount forLSD’s affinity for5-HT receptors, . TheB-adrenergic blocking agents areanother group ofdrugsthathavebeeninvestigated bymeansofelec- 4trostatie potential calculations (77-79). Many ofthese ”canberegarded asderivatives ofphenethylamine (X); ceptors both inthebrain andinperipheral tissues. There areanumber ofother molecules that interact, tovary- ingextents, with 5-HT receptors, including other hy- x droxytryptamines, Theelectrostatic potentialsofthe hydroxtryptamines have been found tohave two char- aeacteristicminimaoneachside(aboveandbelow)ofthehowever,certainthiazolederivatives, suchastazolol ni ve ese(XD),alsohaveB-adrenergic activity(79).Anexami- indoleportions ofthemolecules (74-76). Oneofthese (KI)alsohaveB-adrenengic activity(79).An isassociated withthehydroxyl oxygen, theotherwith aUlOn.of theealtulated VF)for(oarpheeethuleminethesix-membered ring When an“orientation vector” Tesenting fiveofthesecompounds (fourphenethylamine was drawn foreach hydroxytryptamine, connecting thesetwominima alongthepotential gradient between * osthem,itwasfoundthatthedegreetowhichthedirection fNvccs-er-anyern byofthis vector deviates from that in5-HTT isrelated to epee the relative affinities ofthe two molecules for 5-HT ’ a % receptors. This isinterpreted asreflecting differences inthe preferred orientation ofeach ofthe molecules n relative tothe receptor. ‘This lineofreasoning explains theexperimental find- ingsthat5-HTandd-lysergic aciddiethylamide, IXderivatives andtazolol) revealed thatthepredicted(LSD), actonthesamereceptors (74-76). Thiswould reactivities toward electrophiles oftheringportions ofnothavebeenanticipated onthebasisofthestructures thesemolecules decrease inthesameorderastheit6ofthetwomolecules; itturnsout,however, thatthe adrenergic activities (79),Thisobservation representsCz=Cjs double bondinLSDproduces aminimum inaunifying linkbetween thephenethylamine andtheVCP)thatmimies theoneassociated withthehydroxyl thiazole seriesofB-adrenergie agents, andalsosuggestsgroupin5-HT.Asaresult,theelectrostatic potential thatanelectrophilic groupoftheadrenergie receptorinteracts with theringportions ofthese molecules. 0 Proceeding nowtotheareaofenzyme-supstrate in- [teractions, ithasbeen possible todifferentiate between three classes ofmonoamine oxidase substrates onthe basis oftheir electrostatic potentials (80). Theexperi- wey, mental distinetion between these classes isbased onthe rI observation thatsomesubstrates (typeA)areinhibitedbs byClorgyline (V-2,4-dichloro)phenoxypropyl-N-methyl- 2propargylamine}, others (type B)byDeprenil [N-phe- ats yen nylisopropyl-N-methyl-propargylamine}, andyetoth-owen ers(types AandB)arepartially inhibited byboth.Theminimainthecalculated electrostatic potentials ofthese ofLSDshows thekeyfeatures thatarerequired for substrates weredivided intofourcategories, dependingthemoleculetointeracteffectively with5-HTreceptors. upontheportionofthemoleculewithwhicheachmin Whenacompound withastructure similartothatofimumisassociated. Analysisofthedistances andangles LSDbuthaving nocorresponding double bondwastested between these minima revealed patterns thatallowone 198 POLITZER ETAL. topredict whetheragivensubstratewillbetypeA,B,a8mightbeinvolvedintheinteraction betweenthe orAandB.Furthermore, thesameapproachwasfoundhydrocarbon andthecytochrome P-450system.Through tobeeffective indealingwiththeB-carboline familyofsuchreasoning, andbyreference tothehighlycarcin-inhibitors (81). ogenic benzo(a)pyrene (XID), itispossible tooffer an Another example along these lines isprovided bya very recent study ofsome inhibitors ofglyoxalese I(82). For agroup ofsuch molecules, allofthem diols, therewasobserved anapproximate correlation between in- OO hibitory activity andthedistance between thepotential minima associated with the hydroxyl groups. Onthe basis ofthis correlation, other potential inhibitors of glyoxalese Iwere suggested. a ‘Apartial listing ofthenumerous other drug-receptor * andenzyme-substrate systems that have been studied explanation forthefactthat 5-methylehrysene isahighly bymeansofelectrostatic potentials wouldinclude mor-_potentcarcinogen, whilechrysene (XIII)andallofthephineandsomeofitsderivatives (83), carboxypeptidase other monomethyichrysenes areatmost weakly active (84,85), inducers ofaryl hydrocarbon hydroxylase (86), (102). dihydrofolate reductase inhibitors (87), serine protei- nases (63,88), promazine and cloropromazine (89), and carbonicanhydrase(3,90). @@)ChemicalCarcinogenesis OO The useofelectrostatic potentials instudying chem- . icalcarcinogenesis hasfocused primarily upon twoclasses ofcarcinogens, thepolycyclic aromatic hydrocarbons al and the halogenated olefins, with some limited appli- ‘The epoxide metabolites ofthe polycyclic aromatic cation todimethyl-N-nitrosomorpholine (91). There is hydrocarbons and thehalogenated olefins areknown to considerable evidence indicating that thecarcinogeni- alkylate nucleic acids, forming covalent bonds tonu-ceally-active formsofthearomatic hydrocarbons and—cleophilie sites(92,96,105,106). Inthecaseofvinylchlo-many ofthehalogenated olefins aremetabolically pro- ride, for instance, ithas been suggested that theducedepoxides (92-97);indeed,inthecaseofthehy-carcinogenicity ofthis molecule isdue tothe formation drocarbons, themetabolic process involves several steps ofaDNAadductinwhichthe—CH.—CHO groupbonds andtheultimate carcinogens areapparently diol epox- toN;ofguanine (V); this was shown tobetheprimary ides. The formation ofthese metabolites isbelieved to invivo DNA alkylation product ofvinyl chloride occur viatheinteraction ofthehydrocarbon orolefin (105,106). {Onthebasis ofourcomputational studies ofwithanelectrophilic oxygen species, through theaction _thechlorinated ethylenes, wehaverecently proposed ofthecytochrome P-450 enzyme system (98). Aknowl- two possible mechanisms fortheformation ofthis key edge oftheelectrostatic potentials ofthearomatic hy- alkylation produet (107,108). drocarbons andtheolefins canaccordingly provide useful Wehave now calculated theelectrostatic potentials insights intotherelative tendencies ofvarious ofthese _fortheepoxides of21different olefins, withvaryingmolecules toundergosuchmetabolic processes. Forex-carbonchainlengthsanddegreesoffluorine and chlorine ample, calculations forthechlorinated ethylenes show substitution (09,110). The magnitudes ofthepotential thenegative potential associated with thedouble bonds minima associated with theepoxide oxygens (V,,,) were toweaken markedly with thesubstitution ofadditional found toshow adefinite pattern, which canberelated chlorines (99). This isingeneral agreement with the tothenatures ofthegroups attached totheepoxide -known reactive behavior ofthese molecules, and also ring, Ifethylene oxide istaken asareference point, with their carcinogenic activities. Vinix becomes less negative ashalogens areintroduced, V7) has also been computed foranumber ofthe theeffect being stronger when thesubstituent isdi- polycyclic aromatic hydrocarbons (100-103), aswell as rectly onthering and also being stronger forchlorineforsomeoftheirmetabolites (102,103). Onthebasisofthanforfluorine. Aliphatic hydrocarbon substituentourresults forthehydrocarbons, wesuggested that a groups cause V,,,, tobecome slightly more negative. keyfactor intheir earcinogenicities may bethepresence" Two useful relationships involving these oxygen po- oftwo ormore regions ofsignificant negative potential, _tential minima have been discovered (109). First, there appropriately located inthespace around themolecule isagood hyperbolic correlation between thepower of (Z01). [One ofthese might betheso-called Kregion, theepoxide toinhibit epoxide hydrase (anenzyme that which haslong occupied aprominent place inthetheory catalyzes epoxide hydrolysis) andthequantity V,,.,/E, ofpolycyclic aromatic hydrocarbon carcinogenesis (104).] where £,isTaft’s steric substituent parameter. TheOnecanspeculate thatthesenegative regionscouldexistenceofthis correlation supports theidea that among, conceivably berequired forsome recognition step, such thefactors determining thedegree ofinteraction ofan MOLECULAR ELECTROSTATIC POTENTIALS 199 epoxide with epoxide hydrase are the electron-with- accelerated bytheincreasing availability ofprograms drawing tendencies ofthesubstituents onthering(which tocompute electrostatic potentials; anexample isDEN- arereflected inthevalue ofV,,,) andstericeffects (111). POT (113), designed tobeused inconjunction with the Wehave also shown that there isarelationship be- GAUSSIAN 10abinitio SCF program (114), while tween thecarcinogenicities ofthese epoxides andV,,, GAUSSIAN 19already contains itsown electrostatic (109). Among theepoxides considered, those that are potential routine (115). established carcinogens have themost negative V,,;, Future developments willundoubtedly include anin- values, while theinactive orweakly active ones have crease inthenumber andquality ofelectrostatic poten- lessnegative Vj. Interms ofourcalculations, inwhich tials being obtained byexperimental methods (14-18), anSTO-3G basis setwas used, thecutoff comes ata andprobably alsoagreateruseofelectric fields, whether Vin ofapproximately ~30keal/mole. These results sug- calculated ordetermined experimentally, tocomple- gest that epoxide carcinogenicity isassociated with ament electrostatie potentials inanalyzing molecular re-relatively strongnegativepotentialinthevicinityoftheactivebehavior. ‘Theelectricfieldvectorshowstheoxygen, although this isundoubtedly only oneofthe direction oftheelectrical force feltbyacharged particle factors thatareinvolved. Nevertheless, onthebasis of atanypoint inspace, while itsmagnitude isdirectly thisrelationship several epoxides ofunknown activities related totheinteraction energy ofthefield with apoint were tentatively predicted tobecarcinogenic (109). dipole atthat point. The electric field canaccordingly Inourdiscussion ofnucleic acid electrostatic poten- beused tointerpret andpredict molecular reactivity tials, itwasmentioned that thepotential minima ofthe toward polar species just astheelectrostatic potential nucleic acid bases become more negative inproceeding isused forcharged systems. Some analyses interms oftonucleosides, nucleotides, singlehelicesanddouble electricfieldshavealreadybeenmade(72,116-118), and helices, andthat this isconsistent with aparallel in- their number willsurely increase. ‘Thus, theapplicationcreaseinreactivity toward carcinogens (65,69,70). A_oftheconcepts ofelectrostatics inthestudyofchemicalmore specific success isthatthese calculations correctly reactive behavior continues toexpand. predict thereactivities oftheamine groups inDNA to . < decrease intheorderNH,(guanine) >NH,(adenine) >, Weexpressourappresiation ‘theU8Eavironmenta Protection NH,(cytosine), eventhoughthisisnottheordering of—MCV"(GhEasaes O10tePeterPolitzer,Thecontentsdenotnee. their potential minima intheisolated bases (70). essary reflect theviews andpolicies ofthe Environmental Protection Inaddition totheelectrostatic potential, thesenucleic Ageny, nordoesmentoftradenames orcommerdal products acid studies have also focused upon asecond property, _<ensttute endorsementorrecommendation foruse.Wearealsogra thestericaccessibility (65,70,71,73). Thisisadefined {forthefinancialsupportprovidedbytheUniversityofNewOr- quantity, which isintended toindicate howreadily, in ™ terms ofsteric hindrance, cananactive site canbeap- proached.Intheseetuies,theteresecesility ofan REFERENCES atomhasbeenexpressed asthefractionofitsvander « iWaalssurfaceareathateanbecontacted bya“probe” 1Seco,E.andTomas.Thecerancesphereofradius1.2A(thevanderWaalsradiusofa inCurrentChemistry, NewConeeptsIL,No.42.Springer.Ver~hydrogen atom) without touching the van der Waals lag,Berlin, 1973, pp.5-170 surfaces ofanyneighboring atoms. 2%SefoccoyEandeas.Bietroniemoecsar statureren Considerationofbothelectrostatic potentialsandsteric tivityandintermolecular forces:aneurstcinterpretation by accessibilities cansometimes leadtoconflicting results, meansofecrestatemolecularpotentialAdv.QuentumChem Forexample, C,ofguanine, known tobeareactive site 8,Politzer, P.,andDaiker, K.C.Models forchemical reactivity. toward thecarcinogen N-2-acetylaminofluorene, hasa teTheFofeCaney inChemiry (BM:Deb.) Vin accessibil 1 * Nostrand Reinhold, NewYork,l, = greatersteric sibilityinZ-DNAbutamareneg: 4.Politzer,P..andTruhlar,D.G.(E48).ChemicalApplications ativeV°7)inBDNA (73).Recent experimental evi- OfAtacand Molecular Electrstatie Poterias, PlPress, dence indicates thatthismolecule hasapreference for NewYork, 1881 B-DNA (172), implying that inthis instance theeffect 5,Moller, C.,andPlesset, M.S. Note onanapproximation treatofthepotentialisgreaterthanthatoftheaccessibility. rentformany-clectron systems.Phys.Rev.46:618-622(1938) 6Cohen, Bf,andDalgarno, A.Stationary properties oftheHar- . trea aproxinatin, Pro.Phys.Se.(onion) TE:78-730 Discussion 1,Popes. A.andSeeger, R.Electron densityinMoller-Pleset‘Thispaperhassurveyed theuseofcalculated molec- ‘theory,J.Chem,Phys.€2:4568(85).ularelectrostatic potentials inelucidating andpredict. &Bamacsors. Pullman, Somesn, E>andTomas, N-ingthebehavior ofcertaintypesofbiochemical systems. Matenoecularpotentials: ChenPhys,Letters12:622-024 ‘This represents only asmall portion ofthetotal range asm °ofapplications ofthisapproaeh,inmanyareasofchem- 9.Gh,andToma,J.Theprtoatinofthreemembered istry(4).Theelectrostatic potentialisrapidlybecoming, ringmoietlestheabinitioSCFversustheelectrostaticpeturearegularly usedtoolinthestudyofmolecular reactiv- —_jq,Gitte*ytenanproach; Thearet.Chiactaatk areg oolinthestud “Alm,J,andStogard,A”Acomparaiive studyofelectrostatic ity,inbothacademic andindustrial research, andindeed potential mapsobtained withdifferent basissets.Chem. Phys.itsusemaysoonbecomeroutine,Thistrendwillbe Letters28:418-20(1978). 20 POLITZER BTAL. 1Perahia, D.,Pullman, A.,andBerthod, H.Anabinitio study ing.In:Homoatomie Rings, Chains andMacromoleculesofMain- oftheeffetofthe3dorbitalsofphasphorusontheproperties GroupElements(A.L.Rheingold,Ed.),Elsevier,Amsterdam, ofthe phosphate group. Theoret. Chim, Acta40:47-60 (1975). 1977, Chap. 4 12,Catalan,andYanez,M.Atheoretical studyofprotonaddition 98.Politzer,P.,Landry,S.J.,andWarnheim,.Proposedpro- tooxirane, asiridine, and2azirene. J.Am. Chem. Soc. 100: cedureforusingeleetrostatie potentialstopredictandinterpret 1386-1401 (1978), rucleopilie processes. J.Phys. Chem. 86:4767-4771 (1982) 18,Petrongolo, C.,Preston,H.J.T,andKaufman,J.J.abinitio34,Bell,R.P.‘Thetheoryofreactionsinvolvingprotontransfers, LCAO-MO'SCF calculationoftheelectrostatic molecularpoten- roe.Roy.Soe.LondonA154:414-429(1996).tislofchlorpromasineandpromazine.Intemat.J.Quantumhem,35.Evans,M.G.,andPolanyi,M.Furtherconsiderations onthe 13;457-468 (97). thermdynamis ofchemical equilibria andreaction rates. Trans.14,Bentley,J.Determination ofeleetronieenergiesfromexperi FaradaySoe.32:1883-1960(1988),rentalelectrondensities.J.Chem.Phys.70:158-164(1979. 38.Dewar,M.J.S.TheMolecularOrbitalTheoryofOrganieChem- 18.Fink,M.,andBonham,R.A.Electrostatic potentialsoffree istry. McGraw-Hill, New York, 1969, pp.254-288,moleculesderivedfromelectrondiffractionresults.In;Chemical 37.Almlof,J.,Haselbach, E.,Jachimowiez, F.,andKowalewski,J. ‘ApplicationsofAtomieandMolecularBlectrostatiePotentials Blectrostatiepotentialfedandnucleophilicity of35,8,10etra- @. PolitzerandD.G.Truhlar,Eds),PlenumPress,NewYork, rmethyl-aceheptylene, Helv.Chim.Acta58:2403-2408(197) 1861,pp.99-122, 38.Haselbach, E.Aviolation ofthechemical non-erossing rule. 16,Trublar, D.G,Effective potentialsforintermediate-energy elee- ‘Tetrahedron Letters,1970:1543-1546 tronseattering: testingtheoretical modelsIn:ChemicalAppli- 89.Politzer,P.,andHedges,W.L.Astudyofthereactiveprop- tationsofAtomicandMolecularElectrostatic Potentials(P ertiesofthechlorinatedethylenes.Internat.J.QuantumChem., PolitserandD.G.Truhar,Eds.),PlenumPress,NewYork, QuantumBiol.Symp.No.9:307-819(1982) 1981,pp.123-172. 40,Hopkinson, A.C.,Lien,M.H.,Yates,K.,andCsizmadi,1.6. 17,Spackman,M.A.,andStewart,R.FP.Electrostaticpotentials Quantumchemicalstudiesonelectrophilicaddition.Il,Reaction inerystals. In:Chemical Applications ofAtomic andMolecular ofchlorine withethylene. Theoret. Chim, Acta44:385-998(1970. Electrostatic Potentials (P.Politzer andD.G. Trublar, Eds), 41.Charton,M.Olefinicpropertiesofcyelopropanes. In:Chemistry Plenum Press, NewYork, 1981, pp.407-426. ofthe Alkenes, Vol. 3).Zabieky, Ed.), Interseience, NewYork, 18,Moss, G.,andCoppens, P.Pseadomolecular electrostatic po 1970, pp.511-A10,tentialsfromX-raydiffractiondata.In:ChemicalApplications 42.Politzer,P.,Domelsmith, L.N.,Sjoberg,P.,andAlster,J.‘ofAtomicandMolecularElectroniePotentials(P.Politzerand Blectrostatie potentialsofstrainedsystems:nitrocyclopropane.D.G.Trublar,Eds),PlenumPress,NewYork,1981,pp.427~ Chem.Phys,Letters92:366~370 (1982).he 48,Tomasi,J.Electrostaticmolecularpotentialmodelanditsap- 19, Politzer,P.,andHarris,R.R.Propertiesofatomsinmolecules plicationtothestudyofmolecularaggregations. In:Molecular 1A.propaseddefinitionofthechargeonanatominamolecule Interactions, Vol.8(H,RatajezakandW.J.Orvile-Thomas, 5.Am. Chem, Soe, 92:6451-6454 (1970), Eula), Wiley, New York, 1982, pp.119-18120,Politzer,P.andMullen, RS.Comparison oftwodefinitions 44,Srebrenik, S.,Weinstein, H.,andPaunez,R.Analyticcaleula- ‘ofatomiccharge,asappliedtohydrogenlouride.J.Chem.Phys. tionofatomicandmoleculaelectrostatic potentialsfromthe55:5185-5186 97D, Poissonequation.Chem.Phys.Letters20:419-423(973). 21, Jul,A.Onthedescription ofmoleculesusingpointchargesand45.Mo,O.,andYanez,M.Influenceofpolarizationfunctionson ‘lectrie’moments.In:TopiesinCurrentChemistry, Vol.58 molecularelectrostatic potentials.Theoret.Chim.Acta47:283 Springer-Verlag, Berlin, 1975, pp.1-37. 215(1978), 2,Polals R-On thedefinition oftheatomic charge inamolecule. 46.Rein,K.,andRabinowitz,J.R.,andSwissler,TJ.Quantitative ‘TheoretChim.Acta80:21-30(1978) examinationoftheapproximations inthemonopoleanddipole 28,Bonaceorsi, Ry,Pullman,A,Seroceo,E.,andTomasiJ.The theoriesofintermolecular interactions.J.Theor.Biol.84:215- molecular clectrostatie potentials forthenucleic aidhases: ad- 218(1972,see ene aidSine, Theoret, Chinn, Acta24;51-60 47.Stamatiadon, M.N.,Swissler, T.J.,Rabinowitz, J.R.,andas, ein, R.Complementary DNA baseinteractions: application of 24, Brookes, P.,and Lawley,P.D.Themethylation ofeytosineand recentlyrefinedelectrostatie interactiontheory.Biopolymers1 cytidine,J.Chem.Soe,148-1351(962). 1217-1234(1972), 25,Jurdetaky, O.,Pappas,P.-andWade,N.G.Protonmagnetic 48.Rabinowitz, J.R.,Swissler,7.J.,andRein,R.Towardsanresonancestudiesofpurineandpyrimidine derivatives. IX.The interaetion theoryforlargemolecuies. Int.J.QuantumChem,protonation ofpyrimidines inacsolution.J.Am,Chem.Soe. 6S;358-361(1972. Srtest-1658 969). 49,Goldblum,A.,Perahia,D.,andPullman,A.Useoftheoverlap 26,Lawley, P.D.Effects ofsomechemical mutagens andearcino- multipole expansion forapproximating molecular electrostaticfansoynucleic acids, Progr, Nucl,AcidRes.Mol.Biol589. potentials. Internat.J.QuantumChem,15:121-129(1979) {31(966). 40,Lavery, R.,Etchebest, C.,andPullman, A.Calculation ofthe 2,Sualts, DJ.,Maral,L.G.,andKistenmacher, T.J.Secondary roleelectrostatie potentialfromamultipoleexpansionbase interactionsandtheitrolesinthemolecularconformation ofonlocalizedorbitals.Chem.Phys.Letters85:205-270(1982) seeeanetalperimidinecomplexesInorg,Chem,12026. 51Etchebest,C.,Lavery,R..andPuliman,A.Theeaeultionof 2081(1975). rolecular electrostatic potentials fromamultipole expansion2s,Saalds, D.J.,Marzi, L.G.,and Kistenmacher, 7.4.Dipeptide- basedonlocalized orbitals anddeveloped attheircentroids: ac metal-nacleosde complexesasmodelsforenzyme-metal-nuleie curaeyandapplicabilityformacromolecular computations.The- acidternaryspecies.Biochem.Biophys.Res.Commun,63:601— oret.Chim.Acta62:17-28(1982). 051975). 52,Pullman, A.,andBerthod, H.Electrostatie molecular potentials29,DavNF,Wallace,F.A.,andDavidson,N,Spectrophoto- inbydrogen'bonded systems.Theoret.Chim,Acta48:268-277metricstudyoftheprotonatisn ofundenatured DNA. Biochem. sts).Biophys, Res,Commun, 1:812-817 (1858). 53,Pullman, A.,Zakreenska, C.,andPerahia, D.Molecular elee-20.Mely,B.,andPullman,A.abinitiocalculations oneytosine, trostaticpotentialoftheB-DNAhelix.1.Regionoftheguanine- thymineindadenine.Theoret.ChimActa,18:278-287(1969) cytosinebasepair.Internat,J.QuantumChem,16:395-408 831, Tomasi,5.Useoftheelectrostatic potentialasaguidetoun.5(1079). dontanding mlecalur properties. IneChemical Applications of 54Aubert-Frecon, M.Spheroidal multipolar expansions forinter-‘Atomic andMolecular Bleetrostatic Potentials (P.Politzer and molecular energy inerystal theory. I.Formalism, Chem. Phys D.G.Trublar, Eds.) Plenum Press, NewYork, pp.257-294 3:$4857 UST).42,Politzer,P.Physicalaspectsofmain-group homonuclear bond- 88:Decoret,C., Tinland,B.,Rover,JL,andAubert-recon, M MOLECULAR ELECTROSTATIC POTENTIALS 201 Electrostatic potentials forsome non-epherical organic mole- trostatie potentials asdeseriptors ofmolecular reactivity: thecles:anoblate-spheroidl dipolarapproximation. Thearet.Chi, basisforSomesuccessfulpredictions ofbiologicalaetvity.In“Acta56:125-131 (1980), Chemical Applications ofAtomicandMolecular Electrostatic 56.Bonaccorsi, R.,Ghio,C., Seroceo,E., andTomasi,J.Theeffect Potentials(P.PolitzerandlD.G,Truhlar,Eds),PlenumPress, ofintramolectiar interactions onthetransferability properties NewYork,1981,209-334 ‘oflocalized desriptions ofchemical groups. IsraelJ. Chem. 18: 77,Petrongoo, .,andTomas,J.Theuseofthe electrostatic mo: 108-128 (1980), lecularpotential inquantum pharmacology. Iabinitioresults. 51.Naray-Stabo, G.Electrostatie isopotential maps frlarge biom- Internat. Quantum Cher, Quantum Bil, Symp. 2181-190 dlecules. Ioternat. J.Quantum Chern. 16:255-272 (197). a9). 58.Bonaccorsi, R., Serooeo, E., and Tomasi,J.Anapproximate 78,Martin.M.,Carbo,R.,Petrongoo,C., andTomasi.J.Structure- ‘expressionoftheelectrostatic molecular potential intermsof activityrelationships ofphenethylamine. Acomparison ofquan- completely transferable groupcontributions J.Am.Chem.Soe. tammechaniealSCF“abino”andsemviempiriealealeulations $9:4546-4354(977. Jum,Chem.Soe,97:1388-1347(975). 58,Agresti,A.,Boraccorsi, R.,andTomasi,J.Anapproximate 79,Martinelli,A.,artPetrongolo,C.abinitiostuoftheinternal ‘expression ofthe electrostalie molecular potential forbenzenic rotation anofthe eletrosatie molecular potential ofa modelcompounds. Theoret.Chim.Acta58:215-220(1979). compoundoftazololandcomparisonwithsimilarcompounds.J 60,Martin,D.,andHall,G.G.FSGOpointchargemodels.Theit Phys,Chem.St;105-108(1880), accuracyandlextension tohigherGuassians. Theoret. Chim. $0,Martin, M.,Sanz,F.,Campillo, M.,Pardo,L.,Perea,J.and ‘Acta59:281-290(195). Turmo.J.Quantumchemicalstudyofthemolecularpatternsof 61.Hal,GG.Approximate electricpotentials,Theoret.Chim,Acta MAOinhibitorsadsubsteates.Internat,J.QuantumChem,23: 6:d57-364 (1983). 1627-1681 (1983), €2. Cox,&R.,andWilliams, D.B.Representation ofthemolecular 1,Martin,M.,Sanz,F.,Campillo,M.,Panto,L.,Perez,J,and electrostatic potentialbyanetatomiechargemodelJ.Comput. Turmo,J.Quantumciemicalstracture-ttivity relationships on Chem, 2:304-828 (1981). B-earbolines asnatural manoarnine oxidase inhibitors. Internat.68,Kollman,P.A.,ardHayes,D.M.‘Theoretical caleuations on {1QuantumChem.28:1643-1652(1959)proton-transfer enengetis:studiesofmethanol,imidazole,formic 82,Thomson,C.,andBrand,R,Theoretial investigations ofthecid, and methanethiol asmodels forserine an eysteine pru- sthucueofpotentialinhibitorsoftheeneymeglyoxalase-. In teases.J.Am.Chem.Soe.105:2955-2961(1981), ternat,J.Quantum,Chem.,QuantumBiol.Symp.10inpress 64, Dearing, A, Weiner, P.,and Kollman, P.A.Molecular me- 3. Loew,G.H.ant!Berkowitz,D.S.Quantumchemicalstudies chanicalstudiesofproflavineandacridineorangeintercalation. ofmorphinelike opiatenarcotieanalgesis:1.EffectofN-sub- Nucl.AcidsRes.9:1483-1497(1981). ‘tituentvariations.J.Med.Chem,18:656-662(1975) 65,Pullman, A.,and Pullman, B.Molecular electrustaic potential $4,Hayes, D.M.,and Kollman, P.a.Electrostatic potentials ofofthencleicacids.Quart.Revs.Biophys.M289-380(198. protelts,2.Reofeletrostaties inapossiblecatalyticmech- 66,Lavery,R.,andPullman,B,Molecularelectrostatic potentials {nismforearboxepeptidase A.J.Am.Chem.Soe.98:7811-7316onthesurface envelopes ofmacromalecules: B-DNA. Internat cag76).41.QuantumChem.20258-272(981) 85,Osman,R.,Weinstein,H.,andTopial..Modelsforactivesites 67.Connally,M.L,Solvent-accessible surfacesofproteinsand!nu- ‘ofmetalloenaytnes IAnN.Y.Acad,Si.367:356-36(198), ‘leieacids,Seicnee221:709-713(195. 6,Cheney,B,V.Structuralfactorsaffetingarylnydroearbon hy- 68, Weiver,P.K.,Langridge, R.,Blaney,J.M.,Schaefer,Rand tiroxvlazeinductionbydivenco-p-dioxins anddibenzofurans. In- Kollman,B.AEleetrostatie potentialmolecilarsurfaces.Pro. teva.J.QuantumChem.21445463(1952) Natl Acad, Sei (U-S.)78:3754-3758(1982). 81,Spark,M,J,Winkler,D.A.,andAndrews,P.R.Conforma- 69,Pullman,B.,Perahia,D.,andCauchy,D.Themoleculareles- tionalanalysisoffolatesundfolateanalogues.Internat.J.Quan- tvostaticpotentialoftheB-DNAhelix.VI.Theregionsofthe tamChetn,,QuantumBiol.Symp.k21-88(1982). tuase pair inpoly(UG.A0) andpoly (AA.dT), Nuc. Acide Res, 88.Naray-Seabo, G.Unusually large electrostatic feleffect ofthe(59821-38081979), buriedaspartateinserineprotemases: sourceofeatalyticpower 0,Pullman,A.,andPullman,B,Blectrostati effeetsofthema- Internat.J.QuantumChem,23:723-128(1983)crorolecular structureonthebiochemical reactivityofthenu-89,Petrongolo,C., Preston,H.J.T.,andKaufinan,J.J.abinitio.tleieucts. Significance forchenical carcinogenesis. Internat. J LCAO-MOLSCF calculation ofthe electrostatie moleularpoten-QuantumChem,QuantumBil.Symp.7:245-259(1980) tifchlorpromazine andpromazine.internat.J.QuantumChem. 71. Pullman,B.,andPullman,A.Nusleophiliity ofDNA.Relation 13:457168(978). tochemicalcarcinogenesis. In;Carcinogenesis: Fundamental 90,Sheridan,R.P.,andAllen,L,C,TheactivesteelectrostaticMechanisms and Environmental Effects (B.Pullman, P.O. P. potentialofhumancarbonicanhytdvase.J.Am.Chem.Soe.103 ‘TWoandH.Gelboin,Eus.),D.Reidel,Dordrecht,Holland,1980, 1544-1550(1981), pp.55-06, 91. Lowrey,A.H.,Hariharan,P,C.,andKaufman,J.J.Molecular ‘2,Lavery, R.,andPullman, A,Themem (most eomplicated mol- calealations with thenonempirial ab-initio MODPOTVIEDDOY ‘ecule) intoday’s quantum chemistry: tRNA™. Molecular po- MERGE procedures, XIV. 2,6-dimothy!-N-nitroso morpholine tential ternus molecular Seld. In:New Horizons ofQuantum andits«-OH isomers: conformationsandelectrostaticmolecular Chemistry (P.-O. Lowdin and B.Pullman, Eds), D.Reidel, potential contour maps. Internat J.Quantum Chem... QuantumDordrecht,Holand,1988,pp.438451, Biol.Symp,8:149-160(1981. 78, Pullman,B.,Lavery,R,andPullman,A,TwoaspectsofDNA$2.Osterman-Golkar, S.,Hultmark,D.,Segerback,D.,Calleman, polymorphism andmicroheterogenety: molecularelectrostatic C.J.Gothe,R.,Ehrenberg, L.,andWachtmelster, C.A.Ab Fotentialandserieaccessibility. Eur.J.Biochem,124:220-238 kgylationofDNA’andproteinsinmiceexposedtovinylehlorde (98).Biochem.Biophys.Res.Commun,76:259-286(1977 74, Weinstein,H.,Osman,R..andGreen,J.P.Themolecularbasis8,Banerjee,S.,andVanDuuren,B.L.Covalentbindingofthe ofstructure-activity relationships: quantum ehemieal reeogmi- carcinogen trichloroethylene tohepaticmicrosomalproteinsand tionmechanisms indrug-receptor interactions. In:Compater- toexogenousDNAinvitro.CancerRes.88:776-780(1978),AssistedDrugDesign,ACSSymposium Series,No,1Z(E.C. 94,Bartsch,H.,Malavelle, C.,Barbin,C.,andPlanehe,G.MurOlson and RE.Christofersen, Eds.), American ChemicalSo tagenieandalkylatingmetabolites. Arch.Toxical.Al:249-279 ciety, Washington, DC, 1979, pp.161-187 as75.Weinstein, H.,Osman,R.,Toplol,S,andGreen,J.P.Quantum 9.Tsang,W.-S..andGriffin,G.W.MetabolicActivationofPoy chemical studies onmolediur determinants fordrug action. Ann. clear Aromatic Hydrocarbons. Pergamon Press, London, 17 Ne¥. Aca Sei,SOT: 34—448 (IE. 16,Harvey, R.G.Activated metabolites ofcarcinogenic hydrocar-76,Weinstein, H.,Osman,R..Green,J.P.,andTopil,S.Elee- bons.Acets.Chem,Res.14218-225(981). me POLITZER ETAL, 97.Woo,YP,Lai,D.,Arcos,J.C.,andArgus,M.F.Chemical ertiesoffas dichlorooxiraneinrelationtothecontrasting ear: InductionofCaneer, VolIIIB.Academie Press,NewYork, cinogenicities ofvinylchloride andfraws-dichloroethylene, 1984,section5.2.2.1. Internat, J.Quantum Chem., inpress, 88.Guengerich, F.P., andMacdonald, T.LChemical mechanisms 109,Politzer, P.,undLaurenee. P.R.Relationships between the ofcatalysis byeytochromes P-450: aunified view. Acets, Chem, electrostatic potential, epoxide hydrase inhibition andeareino-Res.17:$-16(1989) senicityforsomehydrocarbon andhalogenated hydrocarbon 98. Politzer, P.,and Hedges, W.L.Astudyofthereactiveprop-epoxides.Carcinogenesis, inpress, ertiesofthechlorinated ethylenes. Internat.J.QuantumChem., 110.Politzer,P.,andLaurence, P.R.Halogenated hydrocarbonQuantumBiol.Symp.8:307-319(1982), epoxides:fuctorsunderlying: biologicalaetivity.Internat,J. 100,Politzer,P.,Daiker,K.C.,andDonnelly,R.A.Molecularelec- QuantumChem.,QuantumBiol.Symp.11,inpress.trostaticpotentials: anewapproachtothestudyofthemetabolic 111.Hanzlik,R.P..andWalsh,J.S.A.Halogenated epoxidesand andcarcinogenic activities ofhydrocarbons. Cancer Letters2: related‘compounds ininhibitorsofepoxidehydrase.Arch, 17-2197. Biochem,Biophys.204:255-263(10), 101. Politzer, P.,and Daiker, K.C.Acomparative analysis ofthe 112. Sartella,R.M.,Granberger. D.,Weinstein,I.B.,andRich,A. electrostaticpotentialsofsomepolyeyelicaromatichydrocar InduetionoftheZconformation onpoly(G-aC)-poly(aGdC) by bbons.Internat.J.QuantumChern.,QuantumBiol.Symp.4:317~ bindingofN-2-acetylaminofluorene toguanineresidues.Proc 325(1970). Natl.Acad.Sel.(U.S.)78;1451-1455(1981) 102.Hariharan, P.C.,Kaufman, J.J.,andPetrongolo.C.Electro-118.Peeters,D..andSana,M,DENPOTPROGRAMS. Quantum Staticmolecularpotentialeontourmapsgeneratedfromab-initio Cherm.ProxvamExch,Ll:360(1978).MODPOTIVRDDO/MERGE wave functions ofcarcinogenic 114. Hehre, W.J.,Lathan,W.A..Ditehfield,R.,Newton,M.Di, benzo(a)pyrene anditsmetabolites. Internat. J.Quantum Chem., andPople.J.A.GAUSSIAN 70:abhitioSCF-MOeeleulations QuantumBiol.Symp.6:223-257 (1979), fonorganicmolecules. Quantum Chem,Program Exch,11:236 108. Hariharan, P.C., Kaufman,J.J.,andPetrongolo, C,Blectro- cass), Staticmolecularpotentialcontourmapsgeneratedfromabinitio 115,Marsh,P.,.andWilliams,D.E.GAUSSIAN-1% DEC-10version MODPOTVRDDOMERGEwavefunetions ofearcinogenie 3 Withproperties package. Quantum Chem,Program Exeh,Bull. methylcholanthrene and itsmetabolites. Internat.J.Quantum, 138-40(98D). Chem.20:1083-1035 (1981), 116.Lavers.R.,anePullman,B.Theelectrostatle fleldofoligona- 104.Pullman, A...andPullman, B.Eleetronie structure andcarein- cleoties: relationship tohydration. Studia Biophys.92:99-110 ‘genie activity ofaromatic molecules: new developments. Adv, (ass)CancerRes,8:117-169(1955). 117.Lavery.R.,Pullman,A.,andPullman,B.Theelectrostatic field 105.Scherer. E..VanDerLaken, C.J.,Gwinner, LM.,Laib, R. ofthecomposite unitsofDNAanditsrelationship tohydration,4J.,andEmmelot, P.Moditfeation ofdeoxyguanosine bychlo- Biophys. Chem, 17:75-86 (1983),‘ethylene oxide,Carcinogenesis 2:671-677(198). 118,Pullman,A..Pullman.B..andLavery,R.Moleculareleetro- 106,Laib,R.J.,Gwinner,E.M.,andBolt,H.M.DNAalkylation staticpotentialrersusfield.Significance forDNAanditsconbyvinyl ehioride metabolites: etheno derivatives ofT-alky'lation stituents, J.Mol,Struct, Theochem i:85-91 (1983),‘ofguanine.Chem.-Biol. Interact.37:219-231(1981), 119,Binkley.J.'S.,Whiteside, R.A.,Krishnan, R..Seeger.Ru. 107. Laurence,P-R.,andPolitzer,P.Somereactiveproperties of DeFrees,D.J.Schlegel.H.B.,‘Topial,S..Kahn,L,R..and chlorooxirane.likely carcinogenicmetaboliteofvinylchloride. Pople.J.A.GAUSSIAN 80:anabinitiomolecularorbitalpro- Internat,J,QuantumChem.25:493-508(1984). serum.QuantumChem.Prog.Exch.13:406(981). 108. Laurence,P.R.,Proctor,T.R.,andPolitzer.P,Reactiveprop.