',/1 1 ./tr .1\,i.

tt ,,

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