',/1 1 ./tr .1\,i.
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I. Introductionto ComputerSimulation
th99ly and ex}-e ment: Computersimulationis a bridgebetween Computersiriulation -}"exact" rcsultsfor a!9l!!9!bl!ag&l modl rcsults_+test Comparetc experimental for ptedictions this model --ttesttheories Compareto theortical rcsults andinterpretexperimental Theorie$and inodelswill help understand Computersimulationislbglgg,bjqdeen nricroscooic-arrd-Erlcrolcllplgp-r9Le4tes: (i Bqlgggl-au4oJion) 4g-rarls e: atomic andComputersimulation-+grtqlg-*ogc,
Microscopic details--madoscopicproperties not a!-ailablg from rcal xpenmen$' Computel simulatioi can Fovide information -measureoents under,extrcms conditions that are experiltrentally prchibitive or difficult
experimentallv o1 cture .lT"1"":l* !!!on,g{ strT impossible di!]culttostudv :q:lli!
to study expe menlally' -molecular events that are1oofast or to,o llow system The complete mathematicnldescriptionofa ilr i ( -/ \iL li.,r -l : "
!/
equatio-n: Nontelalivistig Pchrodinger
,rix, rlt!{R, !) *.&d.s{s- r)
of R: coordinates nuclei !: coordinatesof electrons '9(P't), ruuu"fun.tion for the system
0)
H('r)
- V(qr)'L'*q(F!
r-l 6": rotal energy ofthe sYstem F('t)' Huntilto"iun ii'r thc s)'stem H(R,!) -'\"* ffo**3 7F'o), + r'i+' iR'!)'
{21
4r, kinetic energies ofthe nrclei aod elctrons,respeeiiv_ly al1ntclei and ekctorts potrrtiul of i"tertttion ber*'een
" ;-""t
from the nucli to get &couple theidotion of the electrons
"*"ran -*t' 2 seDaiatequations of til eltctrons (for fixd nuclei) The ffst descril*s tlre motiotr
ta{:i B)d(!;s) = C.rF.}dt;a)
{3)
'Adftie) = r.t +Y14!}
({)
9l5s), "6",ron;"
Nclei) 3'f3i, "l".o.*i" F{8)"*
of on the positions the only function(depends paramettically *uu,-
(functionol only the nucleaiccoidinates) "n.ig,v t';love' suritce on rvhich tbe nucler b" ui"tt"d ns the patettid cntrly
energysurface mohon of the nucli on the potential The second equatioDdescribesthe
t,{n). s*(a)*(R) - ,s4{a)
whele
(5)
.de.{s.)=:.a*+r.dn)
{61
The over the electronicwavefunclion' are coordrnates averaged Eq. I the electronie In move electrons field of thb electrons'This is valid ifthe nuclei are moving in the average of'dfrom Eq.! aadincludes t thanthenuclei. is anapproximation muchfaster
electronic,vibntional,rotational,andtranslationalenergy.ThecorTesponding approximation to the lvavefunction is
= 's{t,a) 'rtie)tta).
' In principle, Eq f couldbe solvedfor
(?)
4rW' undthe" Eq for be 6lcould solved th
a large amountof computatiol(using ab nuclearmotion. But solutionof tsq l requires suchasMNDO' codes suchasGaussianor semiempirical initio quantumchemisty codes ht an usually empirical to39a Thus, MOPAC,etc.). is forcefield) used'
of amount a quantumdynamicsandalsorequires large Solutionof Eq Ois called effectsare qxantummechanical Sincethenucleiarerelatively heavy' the computation. oimotion equations with theNwton's so ofteninsignificant, Eq-! canbereplaced
_dE.,(A:^E.y Er
nR!
{6)
#i\" "ult
rnolaular dyrrar,lrcs "l".ri.al W)to
systern theo we c* *" !f we ar nol interes'tediIr tl''e time "volotion of$e
sldes' la suchasquilitdarn struotr*es"tsansition ;*c$lat staticpropearies T:hisiscalled molcllai m4hanies' rirgis,.ta. dyna6ics molecular of Typicalassumprions tlassicel
st"t") surface {i"' a 2. nr*-li move on d singlepotndal "ltt1"lct"oni"!y-e! rmplljlglfit 3. oolnrial surfacecanbe apprgxCl-4!d bydassic"l ryh-t* 4. nuclarmotion can bedescribd
II. Molecular Mechanical Potentials (Forcefields)
A.classicalfor.eftldcorsisls of:
goal The forefreld is frt to experimentalilata from a'small st ofmolecules'li{hrhe
aod exltapola{eto others}slems Thi inlerpolate that tbe forcefild' ill accwate{y and rlative classir:al forcefiells are fit to reproduceobservablssuch as structu'es
empiricallY The total Potntial is
-U r-
+Vt+IAt+U" +V,,rr
(e)
intractrons A, Intrasolecdar (botrding) termsare given by lntlamolbcularintemalenelgy
to & We needquaritum mechanios
describebondingaccuratelybutcanapproximatebondilgwithsimplephysicalmodels. by atomsa connec&d spnngs' bendingcanbe treatedasif andangle Bond stretching Bonal stretching
14=h0_ey
llarmonic Potential: Morse Potenlisl:
a'))P . vr-trlt - *P(-o{l than harmonlc expensive but more accu@te
is more In general, Morse potential
of Disadvartages MorsePorenLial ' -allows a bond 1ostetch to an unrealistic length pulliDg thc otoms the@ w"uld bc almost no force a sltucturo with long bonds -for rcsults might be obtained might be problematic or nonphysical together -rconvelgellce ial potent ge Disadvanta of harmonic at long distances- )other -too large of a force A-oglebending importatrt structus could b destroyed
!l= a.{e- 9.}'
(torsion angles) Rotatio aroun'l bonds
t torsion aagle cemral form:
Exanrplesl
-tl,vo lefg*dral oalbofls coBledd by slnc+e bond: J trr|Ill':Ral
%-- fltil + ''|c'E{nd}Lhere, 1.2.3.4'6
y. 0V2)lI r.o{34)l -
bond:2 nlinima -doubl,e O{t-ofdane ux- E;z Crosslerfits
vr= O/r&I r - d{2#)l
defo'Brationof a d*aar:systm
of iniemal coordinates 'couptingsbar+eendeforrnations vibntional -rcquircd to eccuratelyrcproducxpeti4er*al -cantecome unst*le far fromminima frequencies
As{i-b){6'-irJ f..{6 -i"Xg -$,
srf{r-ot{f-4)
Potxf
B- Nohbooded iDleracliotrs
Yi+ u." E idtreriorr" gi*n ty Ttienonbordd
Alom-alod or site-siteapproxima(ioD:
.Inreractionb"tqngEg19!,lqiust
asun of in
cti
nugli of the riolcule -Intractionsites risl3lly nterd on 1+le
Extend+d atom iepieseotalion:some |-!]1!?qjf1!igl!4Ei!gl}j!\
atoms to which they ar bouBd
G'l R@ J
\_/
Advantages:
cjqP!!44!-(about - reduces
half of atomsareH's)
-!|c9!$
- H p".iti"". "."^lly t()t *
Disadvantages:
H-bonding - difficult to reprfsent
ejg!-'UYlryPslryqsl'
- lossof stedcellects (i for someanalysis e ' protonNMR) arc - H coonlinates necessary interacfions (Coulornbic) 1. Electrostatic
by &andglseparated of two atoms with charges The electrostaticintePction r'jis o-fthe
form Y c= $q, (1$)
lfletolla:
law: Coulomb's the Angstroms), potentiul"n"tga i" yO * S\sa!lato!-
repel,unlike chargesattract. like charges thenthepotntialenergyot (i e by are If2 charges separbted a medium ',solvent)' corslanl is , ..^.V(t) 332*kcnllmolwhere thedielectric decreases: interaction vacuur . = 1-{00in iiquid hydrocarbons r * 2ior nonpolar . * 50forliquid lvater
nuclei, th net
'fh--ele-cirons nol are on each atom is considgrd.&,Ls!lllP1!!!!9tlo!
th d;st bution deterrDines sh.redequallybet\ 'eenlhe alorns in a rnoleculeThe el'ciron partial ohargoDeachaloi_n.These can bealculatdl]omputalionally CHelPG, RESp' etc' chatge anal.vsis, r)/ moletules Ehctrostatic potDtial euergy of interaction betrYel 2 using \4uliiken
onachatom -usCollombb law btweenparlial charges
-sum over all aloms Ifigltr order moments {typically not palt ofclasrical fo'ceitelds) ."/,'^ Dipole moments $easur o{the polarity ofa molcule -vector quaitity (magnitud and direction)
1't: 'iry
by sign separated a distancer;ljjl -for 2 chergesofequal magtitude q but opposite
-dirctionis*omj9il99Egl!ry!4e
+-J-
for Jor multipleclBrges,addup contributionsof all cha'ges 3 componenis
y4- @l+1$+ r$tt\
Note that /depends on th origin for chargedspecies \./Dipole-dipole inteiactions: simplificatbn of interaction hween 2 neutml moleculeswith dipole mornents rs to
moment blv on applcxirnte the effectofall the charges eachmolcuie a dipole oiinteraction betwen2 dipolut it energy potntial ._,,,ton-d iPole irrteractions: {B) ^ x-'
with dipole ion charged an'l neutmlmolecule sinplification olinteraition betrleen by a dlpole on of all chalges the nutralmoiecule thc momentis to approximate efl'ect moment
an ion and a dlpolels potntial enelgy of interaction bet\\een
..
. v(n) ^ fi '
Polatization permanentdipole moment distorts electronlc pola ze: chalge near molecule with no
dipolemoment distribu{bnofmolecule to createaninduced
it of measure howeasv isto 4!:!9!99ry1!!y!jl!3ryE:lle potarizability:
betweena chargedion and polarized ion - induced dipole intetaction: interaction molecule shown to b but ' ' " 'rssical forcefields' hasbeen typically nol includedln cla polarization ir1\poflant bonding and ion hydrogen needpolarizationtems !n orderto model Example: dissociatio[ in water 2. London-van der Waals interactions
for der The'l'ondon-van waals interactions ?j49ryryLarat-!94ufll v"art:
04
12-6potential: Lennaril-Jones Alsocalled
Yu-
"[(r)"-(;I
02)
welldeptb:e Fti)edy {isirg rapulsive w4l atdistanes tess{&n tt" Bac*grouod: | ,oDdonattractioo -g{crua{o4dipqte jnduaddipole i$teraction fl$ctsatio{ls in+e{*or}ied*iki{te*ioo} occrrs irr one atoa:!
,iu$adroheousditole {d'to
rto'idr il$uees an oppositety dirstd dipole in a toig&oring etoor I -dwaYs.ettrshve
tt(r) = *S
'4foepends the potarizalility {i.e. easeof #@alization of the dedrons) of thegrcups on invol\d van der WaalsrePulsion {stericpulsions) or -all atords molculsrpel at shortdistaats be odgin: ? letronslannot put ioto o'relectronic orbital {uantum mechtrnical diftrent simple modelsavailable illto{ojfet hardaplFr:zerointeractiodqrgy untilbace
sofi spnere:
r{')= #
&is poritive anddepends both atotr$ on rprlsionenergy startsrising betlvel2 aiomswhe+e vander w'adsiadlus: clistaJtce .rapidly C. Ilydrogen bonds vandr Wsalsandlct{ostalrc {n sonre forcelields,hydrogeabondsarisehorn slartdard
5-
bondingienns tenns.Otherforcefields includrrspecialhydrogen lor Backg,ound hldrogenbonds: simultaneodslywith 2 otheratoms -H atominteracts -enthalpYo{j}lSlmol
vss.
(compated to about400 kJ/mol for covalent bonds)
-the most important H-boods in biological systemsoccur with O and N A l.xperimenlal crilerion thal H-bond existsberween and B -if2 atornsare closer than the sum oftheir van de. Waals radii { R 1,5,{for O) ttlen they
I
a.ealmost definitelyH-bonded is -ifA,B=N,OthenifAB distance 23 *3.04 a H-bond exists
solutiondueto competitionwith water weaker in aqueous H-bondbecomes H-bondnet,rork of water: neighbors wateris intemction with 4 tetraie&ally oriented -each -rct rigid (mobile) point, highviscosity, highentropy of proprties ofwater: highboiling -alomalous vapoization and Rcstraints D. Constraints and Theconstraints restraintstermsaregivenby L (i exprcssion bias the calculation e tQ alld Useconstmints rcstraintsto modify the.energy to focusthe calculation on a regionor confomationof interestand to setup
computational experiments) Constraint: an absoluterestriction Restrainl: an energeticbias Fixed afom constraiRts
n f,r* ,.' @' u
(-t \-lr "u .Li {t
/v1
eonst{ain aioms to 6 given location inlollingorly Teflnsin Se energy expression Iasler calculal;on Llresysem is redijced -+mini$ization Nuslber ofdegrees of ireedom ii:r faster ExanPles fix protein ptoi-ein aJ)dBDdel wa{9r strt}cturearound and dynanrics _-',e!ergy ilxed atomscan be eliminaied
ptdict strrctute of celtajn 'eglons -Fix nost ofprotin but Distancerestraints towald a given value folEe tbe distanc between 2 atoms -simple harFonic function:
it =Jf{., - rid'lr}r
413)
of hainonic function {flat-botlomtd -five piecewise continuoxs rgio$s Y 5l +{t1-rj}ft :rrft6-rr|
potential)
:0
- t$t - -I(3it11 r4}ir4 t4 g tit = .{ + {41Advar,tagesof llai-bottomed potential: distances -allolls a alge ofaccePtable -nct neessadly synmetttc
r{ <f1 t!.<*tSr I 12< r r t313 13< r r r St{
disiance eror in determiDed -flat boltom allows for experimenial target wbich avoidshuge forces iffar lrom regionshaveconstantgradisnt -outea
restraints cyclize a st.aight-chain to Example:Usedistance motecuie Torsior restrainfs force a torsionangleto a pa icular value or severalrelated values 6x.-oo;"Y- tr{d -*e",)'
periodic (can restmin torsjon to one of sveml related anglesifh> I ):
v -xE+..s(&-4)1
Templ4teforcing force theconformation moleculeto be similar to a template ofa molecule
r,=*f,Er',-"t"**n*]'o
Y*1fi{a-$@f
(:4)
(151
Eq. !l: givesbestrms fit but individual atomscan deviaiequita bit. Eq. lt: gives worse Ims fit but does not aliow any one atom to deviate as much; allows for diferent force constantfor each pair Example: Templateforcing can be used to assess how easily an analog can adopt the conformation ofa giventemplate Telbering force the atomsto be Similar to their original positions; useone ofth equations for templatefcrcing,typ;cnllythe secondeqlratiol1 Example:Tethering be usedto keep a protein closeto its crystalcoordinates that can so defcctsdue to anifactswon't distort the entirestructure
!1.Hw. ra, ;ru: c i,.iriac{ioDs der \Vaals' l{et x Jepartte iniEriictioB- tssul|sfrom co$bioaton ofln*don, van ell-. inleraclions .(: .1.rci onding 'l';
\tati $'ith rvatei) fiyd-.r'i, i).r;rjt: lvalei fearing {i!'tergcrion nvith \a'ate'less ibvstattle than hyd.i.' i-,\ilic: 'vater loting (strong fal'orable interactions with watet)
(many arni.', rr l:iiic: both hyrLophiiic and h;drop*robic ciraracter in the sallle molecule; base9 ami:c :cjds and.mcleotide
l7t ' '
.:,^ti:.!,, ,r, i.' gqs,-enhopy'dri\'en
.i'tv.l fc,ohcbicitteraclions:,1:w d$a!!c,l]ql
2 hi'ckoca*on groupsR introduced into Ealer wilLclusir hydrophi'lic +lldiophobic amiro ecids in pmtein usually cluster in iderior ofp'otin' atd {he surfaae u'i}erethey interact with water' {cha.ge.d,polar) a{hiro aidstend to be at Polar {ipid ncdeculesform bila!r shels or membranesin \'}ater $'herchydrocarbon parts aie buded insiCeand po'larol charged parts are on the surface
