AMBER, a package of computer programs for applying

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‘Canpte ThyssCommsiens

Computer Pryses

Camnmuneations

AMBER, a package of compuler programs lor applying

molecular mechanics, normal mode analysi

molecular

dynamics and free energy calculations to simulate the
structural and energetic properties of molecules

David A. Pearlman *, David A. Case &, James W. Calehwell
Wilson 8. Ross *, Thomas L, Cheatham Ill '. Sieve DeBolt *
David Ferguson *, George Seibel °, Peter Kollman *!

> pagan oan an Cay So aha 207

‘Egor aon
Beaeton a Winn

Uno Sse Mer

Ne deetibe the doveopmen. cueat feu al sine rine fer fue EStelepen he AMAR

yaslnge of spite pre The pucage hat sce mr pum bacon

Bie nd Enorge Iti nt oa arp of yrea= nal umm of Powell Ls af meer
*
‘Stiputinne shomsge ableton and fe ergy ener

PROGRAM SUSIMARY

ERD (WCST Oba Selene LALO

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TONG WRITE

1 Tatendetion

‘amis gr sce ea a san 10 hs
Gere pbru ig 30) RED posta Te

The cracept at AMBER dates heck 10 187% when Wan! Weiner jo tod Pever Kaliea’s Iahotntey
\Wener bid been stadging molecu mechanics and Kray refinement a8 proc wih Marcin Kasphs
at scvard. ie brght fe ager ends “or cncegy and Carteian snovinste anelyial desea:
‘slualion. developed urinal a 2 We ann Tete [| and refined imped ay lin at Hara
[aL (> UCSI: AL ihe time, mnlenlar mechanics singrars ended: he specialized for given clases af
ratecales A soy Weiner and Kullooa's gol lo ukvelap a conupletoy general molectlar mechuniss
frog, vole uf energy component anasis cad computes graphice display as well as enecsy
Sakenbaors chet cul tne svt ecules wells jjess with arity banaeetcs a cou:
fp vais 9 Tesanatly se Inenlly way, Ihe goal wan eeaced inthe form oF the program AMER. a
fescue i [3 Usiiga tow sewttre fon ad agovihine my generate ends ares, dikedral ages
and "exchaded alors” trom ine hend cotnestion, Weiner spattructed PREP 19 prsuess pligical
Informstion on 3 wie 61 place al LINK (to link residos gether im genera ye). Tee ober
Imadules, FEST (which enaiect monenatnn Ia bs manipulated, and PARM (pbich ype woke
Iacharical partes ont th tt fypen ait esky were costree to feel in MN, tbe enone

Iminnzarion progran. ANAL, + progam (s evaate The moleey ar mechanical energy compements (Ot
shire calles of stony al 1 Semple grips <haplay cvogram cnmplsted the fist version of
RMU

‘Weiner aml Kolhuin ene dortunite 0 be Wace aa Jae saan apartment as the TICS Compocee
Garp Livoraony, whuse Lvans and Sutherland BS! enable el tite colar interacreseompwce
‘rap [1 something sa way svadabe a ew lhe pls a tha tie. was also Yor pros oman
Tha mes Desnny pine Ube Kean lita the line, Destng. with previons experince in gcaphien
rogrours st Oslor.consiucted a geaeral macrmulvate dpa preyrsin CHFM [4 lor marketed hy
Feil Stheshan ay VSSHUW, Unis program an ber, MIDAS [6 developed incre Graphien Lah
provide 3 cousin complement Wy AMBER in studies ul empler macrowalseular sitce Becaus?
‘witout the ability to ecleetvelyvindize and think Lew Sitvensional'y ahs. sptcne.cxeusing
Dl ings coun miler mesiice on then 2 ealrenely Ulf. AlNhoagh CHEM and AMBER
swore not Ghly canpled, communicating simply vn PDB fe, the conglementarty in using ca
Angether gain ieight jlo nucleic atid ad pole stems was ery lex

Sbeafly aller the is! veer of AMBER wae eempleted, David Case nad Pal We-ner incorporated
analytical seered Uenvalves intu the progeam, emabliag nora mole sidysis bv he pe-formed, and
‘Weiner sroke & graph pocgrim us vuole the normél modes- Daring thi time, both cecigy
rainiatin wae none] anades were wed in tbe developnuent of # ro lose fed [FA] which als
tated some chorges dered by fi 0 the eletrntatic potemil [9 Tix ull Ye ews 96 the
cnngletion of version 1 uf AMULK LOL

Wilfred van Ginter hal coven woplemented moleclus thins inte hit progiam GROWOS,
10) Stouad this tna, Kelli aoe! win Gumsecen wa moeling au ncnieed whetbor GROMOS was
alae, (0 he ase ta ingurporvte yoleculs dynamics in AMBER. Van Chunsiesen was willing
make GROMOS waTable, Aliagh Kollmin ray hive been prewient ie his vsion ip the init
construetits af AMBER, hix ensitom fur mulecalar sme wae no! great at tha ine. Lay for
Jim, very talented scien, UC Sigh. had joined ts prop and wt lp run grads sent Seer:
Weince “spliced” the woleculi dbname from CROMOS inly AMBER i very sor: Fe [1213] Ta
dsition, Singh wrole » coolecuie ckmamics angi program, “Ibis cumple thy developtecn! of
AMBER 2 [14

‘At arcu his tn, ports from ‘Teery Lybrand f4 force gradual slodewt at UCST 30 wes
postdoc it Andy MeCammon’s bornury a Hotton) om the we of mahicula fan and staigial
fuechanios tn cxewiate Tree eucige llereace and Ihe appeariice of pegen by Tengensen sd
Ravinitan [15] employing Mune Cielo mielhude und the sme ities! sechaaiel <quation® ta
‘akuate the dfsrnce im aque xbkaiun fee eneagy oF metal snl ethane, gabon Singh and
‘Kollman. Singh thus began in insororate tee sethode-lerned-Lreewneigy peetaation methods” nto
AMBER and. worting with Pr Bach gel Fienk. Bra, ted bis code or hoth syle and eompice
‘stems. Two paper in Scionee [1617] an] ene in. Aroer, Cher, See. [-8] erie the vaethadeng and
two exciting cals applitons. Sirgh algo aukkal wu other ital capabillies 10 AMBER. Te lst
‘was the eapabiiey af Tachid ng nom-chitve elles in moecuhi mechanics using sonic pobre
UBL Singh sto ogupled AMMRET with» ersion of 36 Gann sees af grams ie forre OU-PST [23%
‘cumin uiu.oai/¢nebeadar rncchanies 2xegcem. Tho above calnared she develapesne af AN
BER IEA

‘A thls pol AMBER bal become tke an ovesgruwn cl, unruly aut diic t0 manage.
Fonts, George Selbel 4 LCS graduate student at ie liane unde! Sok tho shanbles tse of
leaning np the cole Ccludiag dsing bes wod caeruay Uiexgeat auchine-secite versions of the
(rogram, implementing a valusiun vite amd brag the celewe tader crUfT mbagement Zor the
fist con This wusk sesukeu su AMBER 3A (22.291 whale cluded ura tesidus-based periodse
Imagiag algosirus, petouriance al rely eimemenis. dl funder eviiens 7 abstract
machine dependncks and esate the Bist generally postabe version Of AMBER. fa pasate. devatop-
ment, David Spellacyet @ porkhrtoral elton, verking wu Willen Supe af TBM Lalo Abo and Frik-
Roheer Frensen a¢ UICSR, began the devclopuneal ofa ue mulceul dpuales module SPASMS (2)

‘Tae arrival of David Powvan at UCSH began lar developmen, of AMRER, 4.35]. Ths major
28ions in AMBER 3. scio a large nner of es cupabals inpcuveonets in CIBBS (Parla),
the free 2neegy module. the aldton of SANDLR. a module nt saltwere fos Lestained MD sad NMR
refgmainn ehament (Case tl Petes an the adion of tbe sspablaly of woaadibs (198 Beks
sn nme grands +Cakive-() uo numa rude saab wultvane (Case! Bil Koss cco at Sebe)s
‘gan zaional work, ailing opilcow ad putibiliy features, et

‘Ponti med dzvelagmenr of the SPASMS module tas been cited oul ty David Ferguson Te passonee
es ako aTawted eomiralis neee-eciivaton of ios mony the wide MTP weclyes a. Swope" €
ideas foe seding op non heat ialerions (aal ave mde Uber wy ss GIS and SANDE)
“Those and the devclopmenie in AMINE 4.1 [2] sou Ub be reese des whe bee

"AMBER ie sos nel 15 yey wa 45 > Cass a AM, tater ee Td 1 a
in a opinion. remained srg cl wal sc of the poe ingyen es all sgovih
Tele the investing compiler pve thi ba enable ce cplicaign fa inkeresrngImlecee. Ti
ism ironic that AMBER hagas ta le feral ina weil lertaee “9 genes a esulae
fechas program a it mow eh ner stat a aol ving ¢ alate grace sce fel
interfice. THis © diz to che somedincs uuxpyceeall lolly el seing oa es malig uch
Interiacss, paricnlty in “sice'y" wish gees email splcaions 2+ methrebigy dceelapmene
rsh mie than akin siting general, geaphiel olsn.ct nerfs, Mopotily, i Xondse
prosrant hy Chaitian Schafer, TSP, [i] an Pear 'c prueeal AMBER /1NTPRACE feat
ne [2] to SANTIER ane GTHAS wl help clove the “interlace gp

ilo. puesene a dcceriptin af he must importa fealuees AMIEL, The aertinne 3:

4. th. soso
E Overiew of the prngears and ms coves

1, basic ideas underlying melenlst mechs ies,

44 incusen af nowvaddtiveeffsr in the peas chcagy uneten

3 SANDER. ite program for enerey miniaisation, moleculadsnamves ad NMR rtinemenss
6

g

CHWS, the pengraa or freee sgy cle alations
SPASMS. a new dynamite onciyy program
INMODL, a pnugeam for nove mace Anas
S Suactural and encrey anal onl
10 INTERACT, a sonpting froneend for SANDER and GIRRS:
YL LSP, a eeaphical racecar builder program
12, Coneluiag remarss.
GOO ©

t
= j= a
Fa
sins

2. The programe source code mauageneat, potabity and performance

“The feo Rigune Pirates the velonckipe hetwcen eke main programs in tke ABUSER esky

AMFFR vipr ginsisty of about 68 proguas, lh 990 9. “es containieg over 332000 lines. ul
wil sb 187000 lanes ace cone, ABER coe ht Uehcvealy Ui ll FORTRAN, but withthe €.1
release. 30% of Ue cues wna C (LEAs 205% of the tut, The rclews: fe wanaged unde: UNIX; the
UNIX versus as Uatibuted euntin al tne cmanagemenl tools iluding the ais to generate source
ile fin aot NUL ters anu lites lor ee cecurive Lip ef sown live In VMS wsachires. ll
‘erslonsinlude ll he sures cuce, An email elles is been see! On acoso ascend
the stauibaler of ou les,

' eumpllitn sytem han beca devked chit allow the veer “0 cnupue every ng 90 ay version of
UBL by oops single lie comaining machine Uependenties rum 9 Katary extn nov 22 rest
UND, then cunning a serine which ‘enkes SO Maetlen. The same syste allows soutee: coke 10 he
seuerated Tor VMS, VM/CMS, DOS. and CTSS apsrating sem. Cabike Ue souiee cute, the
fomilaion system has heen placed in the poh demain. The mzchine dependence les set UNIX
txvironrene ariales wich define enrpst sonymands fr sarions opcimiraisn level, tp we! a varios
Ainge which are eses 10 hy the pp puepaovease: Iw st¥cin cath FORTRAN source le for machine
dependences Cine ing shakey memory aux! maewage passing poraleliam’, which are delimed with
“giftet Fool!” coasiivels Cpp ob tants “iueldde” sTnlcaeat, hh ate ryscaly wed for
common blocks, the exarorunen!visiables are used bya sbell snp. Compl € wich i nenked Py the
“Maksfics te compl. sl Ek Lae CORTRAN programs or Uo sea rss fora gen rischins
Tho machiae fle aly indicates x machine-poutic <iceclury were Dine. sya, Ie blr which oan
uutlude tasic C bray routines saca as gtarg() tn be nked with PORIRAN if the pisevine's
FOLCLKAN hay o deliciel, small Eority al machine-depenueat EOKLIQAY ening pres
mexiC) allows the programs Lo return satus tthe cperating fem: acoupeat) hues vauiacoas in
fpea0: aad seeuruC) and wal) hide dtu nf tou and walla Eming. A portable namel? Ubtty i
tho proviled guciey xf Neksia Beebe. Department of Mathematics tthe Crises of Mak
An xosplioa 9 the souwe muachineepenency system UNE abr SPASMS program. for which. un
suniaey FORTRAS program is povided ln mak (be program's swurce voile foe anchire dcpendspein.
The has tho wautage of alling une lo bub souroe Ibe any aiachlas oa sy machine (ue. the
rmanageurcwaichiaw does not aed Wo be UNIA? A disivaalage i lh machine dependencice ane
rush Farce proelam 2 ie wankiuy programy, Sone UNEX tools ew als sn provided to spite
fingl exnosical SPASMS snce Oe ilo utany fr fst Jecomplaton of inevigual modules Curing
fecelopment, and temorge then ink the cazenieal, sage fle form if desi

' demo tis fs prosided wah exaunpes of ruious chica scans, ena enmplementary txt wee
prewied ta nthe co atce consti tl compare the sess ih The lem tree. There i an &
henghetk ce with waety larger splems in water sal vacua 10 2 Ths sped af new sis
and ro cospare che pevforumacs wi sarivus machines

23. Wis for molec mechanies

Molecular mcchuntes is an approach to ropresencing the cnsray sulace for bon! and mu bored
interuions wih a ample. auatieal and cast citfeccniahie energy fenctien. Frum the begins, the
fulloring ruts potential enous Poneto ha® Rees suopartsd i AMBER:

amt 1

I Amber. scsion 1, mininiaation of Gots! poles! enetyy) was supgcrtrd using Som tecpest
sdesont and soajupategradon tsheiques [3] he sme eters aneton, Fade dora, are ase
fu second dervacis maie'sation ud bial mee ave, 4 anced dynamics shratstions wih 9
Setnout rostinty and in foi chy ealltions rere the 7 fir cnealecule” stom en Ne
‘uated ita the 2 for anette

"The phsizal eal af sinulstions ning AMRF oan afer seh pagan pera nthe accuracy
of Lig. (Ub Cae of he strength of AMBER fia Been th ancients of he potential energy fanctinn [29
That fad mast he rena th hie sei sey posing tn cantonal sd nancbanded energies,
sal high ‘reeueney inttmlsenlae mations. Same programs (2g. MMTZ/MIMG [3] and RIOISYME
DISCOVER [31D cappores muh mote complex ene’gh furesion far inttsmelccular intervetions (23.
signer urder term in hones, 7, ages, @ and eoging terns Keccen ches) Ht fen eion
Th if nes focus fs on non-ne and ennf-mac nal energies of ene newts, the Incas oF
Such teres males the rd unceeeartycuttred wih Tle pn in reoresenting he penportce of
teres. Mure importance fares 2 aptimi furhas she nonemdad and clecostatic ein nF,

ciao of onddveefects see ele,
‘One shou.l 3 forget, henevst ther The Het dating chllnge in cmptational aplication of Fa,
{ww wumplex. polymeric moleenss is The ‘real minis problom [33]. 42. the don in aoaaace ly
ie clive ree energy energies in soltiny nfl the impertant pape conformations of

i], This: challenge fr 2h fame
4 Limitation ul Fy. (1, skmale be meted: slectonie srmcture changes (3cied sates. Rona
tweaking nd making! are na representod, Thos, for Slatin of rer ve proseses, anc st ene
‘u..cula mecbanics wilh quartum mechanics as hae en cane by Sigh FAT and Mer” aieco-rkere
C5) ving AMBER,
4, Nonadaltiveextemsluns 1 the Amber emnttonian

Oue of the mujor aierences herecen the clasial physies methods eed tn smuly_ moloanter
‘pce anu the mre rigorous quzatont mechanical mtv i he ably 48 :Fe tart acca fe
‘huge relistbution. These i 9 methed avalabl (9 ad that capa to elsscal Hamitonla. Tht
syyovel Caused potas’ sda plavinable noite ro che Hanlon wich shen intact with cach
fhe sl the ge! apes. In the moet geacral t-te fet chi-goe av the ico unite can
Ds ened al cabiry pone in Space, subset tc che consent thac the ealenlsed peaertics "ese
the melzeute To practi, fixed charges are wll reset tn nentions smzespemding ra the mule ot
the aor (llivugh wally used lr prt mode's he Water are a novaleexecpecnp in Kecoing wk the
eon of pig souas sad bat charge ea aelar eer. Hewever. molecular polarizability igotsh
‘tensor plicuunon anda sack # amenable ting. deserined hy 4 tonne expression. Ti a fe
Gificnl te Cuoune teneen a ‘chemica™ Tande of choosing The platization appecach aad + "wads?
prec Tn lie “benics approuch una of standard cial description (eg. CD, G2 (=D

fea ano reywtentsted by general 333 1, fom

‘The ‘model approach makor the shyaicy vesiabe appecumatiy thal the lems elev Wy mesL
lnvezeating biochemistry can he sete! =< dnionnly deformable iadatible ule desanbed by 4 sngle
piczmerotesentialy ry reseed ta chagoeal uatrc wilh eqn lemon). Tae atankge of the
‘chemical’ aporouch & ca there wil hy far fewer inleractuons 0 comer, Mawever Ibe vomplesity at
the uncerhing macioaatice makes the “iiwlel approve wwe prevent shoe, In this method the
Interaction of the dfygonal pola wuts eh vlber sad the point changes ges vse to meucod
Alipoles at such wteme center

‘be groundwork fortis rade method sas pefermeed in as lboraluny of JB. Applets 36h
sulle the molecular easton of light. "Tal grap deste a small set of a's tar hyde, carbon
nittogen aad exygen in a savers of shenicel ensicunmenis which reprovue the ebserved molecular
Tota [32] aswel asthe cirenla diac xpectea ul polpepides 38). he Kollman group recognieed
acy (at dus etlet was naportane and theese uf he nace polameiien way sue by Kollman dh
Then ha L9KE [39], However, cw on'y posse tering slerwatives ol the idee! polation
term My nunterical methods until the work of Ableinen [40] ‘eval zeae spprvaimiraons tit
Allowed the dcubaon uf unica derzares of tho every ing nyo she itseaclie Ie ncced
Aigtes

Spreng Kivin (41 have describee an alternate ayrouch kt ceprssentng pulatzables whescin
the iniveible quuments ace represented ty post(s Ancialing (im a se-l<unstleal iasraction
Sshome} “ouiebarys” pasitionee show tho "seer uf a gil mmeeralar vail. This apprvsch i
somputatioally spuewhutsipler and works wel Tv water sw hbely to be dla to porameterie
for gencra] maloeules. Suautima and McCain [a hive suggested moniecaiveacheme lu inlide
some of the feet polrizabiig which only sous the waka momen Ws anterast with the ise
charges and ot each vlher

‘The Frcble dipoles ae fit map she AMIBFTE arch a stam elu

Bae LD Roem eg EKG gt EARL Honetna ytd

i+" Bum ‘
a
aw

oT

ei

1m practice there use ms methods to dstormne she inusod fede: (1) Perform 9 walt iverson af
te Ls. Tema ang (2) and ©) eran am inal guess of a induction. iterate bs stable wae of the
induce Gold euthed. Method (1) crac: howeve: (2), tater, anand to Appleguist [3.8 wll
asalequcte 2a the light of al he acherappresmatians tht goto the casical upprosiqata, We awe
tapleriented metbod 2.

“The writ of induce polarization was mplemented i AMBEK by Calévell al Dang 4, flowing
she PD. hess ul Able (40) The spprasimation of 2 uniform dtagoaal walusble Uplate fis
boutwome of exten tests (method 2 ahewc). The program iapments

a 6 0}
- a

‘suck sls fom Jel verison 6 mitho Une wer with Ua minor Wnkering 0 Ut eu eu,

‘Ti aldiwn of sell consivent alone polarization (SCAP) to the aomtal alse Hovaltouaw
inact i» vey slaple manner Tore user. One mezely needs 20 spel alta poze (or
tschr aln Typ inthe iapul ty BARB che sve fase asthe itoune masses an act the "POT.A? Da
Ting Df eda Wn Saal. Cabby and Nrie the user chem vels"spal= Pe dou is 0h

'SCAP is erty aot lives i (peal reyuires 15-3 times ae much CPE line ae tho alive
Finite ss Tu pics. sudtive molecular dyeamies or minimization rua ua Uiqul wf sal wolecule>
fichow SHAKE Gave is Wkly negligible), approeimately Wi of the CPU tte is ceusuaed ia the
oihomisel encgy evaliston. Pur the sure sistem wid SCAP inctaded, dhe CPU Line breaks is
owes voubou! evengy amd derivative evabuation [2-15%% SCI" kuduced fick deteuainalie
531,575, anl SCAP detivalie-valistiun 27-50. This for eamrenging ws (4 KMS dereuos iv the
incigutelectue Bild, We fel Une. hn Ue Insts wolerance Ut useep le he ouneergente i Ye¥
"ap, wall ody requung fe steps tbe Cal RAIS ouch below the cata SCA is exponive fo
fe somewhat rez reasons: (1) Ure singly much more selthmetic Ly Ub; (3 the athe it
cimpletole sak Ils posible that new logs liz mans toversiom walen wilh Randa specie
‘Wik con! aust: el wily the SCH portion ofthe eaclation: tis ur Ue shot Unto Uses ve
Te-sithe + as dorable dlleage to speed up the dersatives,

5. SANDER

SANDER ix the susiu AMEE module which cares out minimvaion, caolewie dbmaies al
NMR rotigsncit. The aciouyay stuns Lor Sioulated Antealing wick NSIR Derived Energy Resa
bt in taet SANDER is pothops met ullea used Lor thi AOL eelted Wo NMI, The te pulscipsl
igecithms contained in whe ode are a conjugte-povlical rocelure «© minionze tbe molecule
rmechinits energy ands) molecular dynamics gooveuiee thot sss the leoptreg Verlel theme [a
propagate the tnjeciry, We Bil discus sone of the geucral foentce of the tod. fullowed Ty
Ujusion uf be BMC specific por ium

54 Bags fess

SANDER proves nest supp fe Tho AMRER, [7.8182] and AMBER /OPLS [45] Loree fed fo
ploleins and nucle eit sal fo the TIPID and TTPSP models for water 35.48, ther typ of
Ptewictere cen be ealered and the aks slows amc variating in fonesonul fox am well in
pinometers, These varitiurs induee elle fouys fr “mplopertonsors und Urey Besley
Frccations, su that force lds Uke tt of version 22 of CICARMMa [23] can be implementa. 3h
‘ililion, wt allie Fonoe Beals based em soxmacatcred dspnic pela ashley can be included,
tlscibed in Beston

‘The elative weights of vor teom ja the force Feld 2m Dy vara oot ie. In wt. is as
stesghifonwae ly fempleacul a gosmetee’ (ores £1 a which ads and angles are kept fed worsens
i Tres sa non banded inforatiggy cues! «ay fa? inavastons w prevent steric esp. This
Set Of pntcotal cag be weft shy ano sanformet asl chanics sre aMcipated, oF Wen Ue is
fonastned that zeus iy the rege fealigue boc peculiar aiasing the result,

“Tan yenmctice sf pial tamaalaty eons we inclded: he eloeseinnage cunventin ix wed
within cher teetangiar patllsepiped nt a tnucate aetaherdeon Ceo wite coraes chuppel <3.
Renbowcod inccictions 98 eorqpat fv Hy: cat inage as lena ae Cs stance i telow sex ase
sautnfl Tae eats ay ouput a a pL Hive Ivy Ls the astance hetteen aay pa af aters
fis hetne the culul all sourpas bstoven thy corsapaading fsidues are included. for neal
Fesiduoy his cgnates That dipmley-e uo! api, with eat Iaafs the uta and the utber ouside
‘Atoan p's Ive Btwcew Gee cal gn] seo Inger cuca! can 36 evaluated a: less egueal
Incerale, and hase thee cpatsbtius tthe Toaces i caeigs temain constant until che next 1oRe Cy
2 updos, ths oplcmenting «wy sole Seven of multplesime-step algoithea

EZ Enya vd nastier sss

Enetgy mruinizaton n SANDER uses @ conunate aradient procetre (83, wually fll og a few
‘eps ut epost dent to amelirase cory had itil energies Alihuugh thes prowhnes ein
fective at finding local main, ic cat often cake mary trations -0 fad accurate mipimn, Ly
<anformtions where the roncmicar-auare of the coments of che gradient i less tan 10°! eal nol
or these problems i car be adranuagenns to ute ths Newtar-Raphsen ot truncited Svwlea (TNPACK
routines #8] that ae implemented in dhe nmode mvole Its alo inereasngl comNur. 1 ws Uspiraes
simulated annealing of sthoe more ‘lahal techniques 19 find low:-2neiy succes.

‘he molectlar denanvcsschowle Sn AMRER basialy fellow ideas ist developed 2a ie CRKOMOS
progzms [11.301 This uses 9 leap-ton’ version of the Verlee algorithm, in wich the posiions ore
Atetermine tines ,¢— fot | 28 and Cio eeacides atime ¢~ 30/2, 7 A172, C58) Zou Bard
Jeng comsamts ate maiotainee with die SHAKE procedure. csi aa intratve peceduee cose “ate
‘sighaally Ueverbed [SU for bonds inthe proteir.or nucleic acid. and a spevial zaalylcal vexsiny for
2 point wcter [2h

“Termperaure roguhwun can either be cecied out by pemadic xealigg of vec, Se by a Wak
‘empling procedure, whece a: every sep che velocities ae slghly made bya fact thst depeads wpe
ihe inlaotaneous and tare: temeeratuxes [SUL This rocedurs w dexael ty buve the nystetn (er
luce appeeceh the Large leoperaruce in an exponential fesh-en, with alle cemstoat sl By the sen.
hualy ia che range of US Wo? pa although Jooger valves can be wed Lue aon spe im a imate
snveilay eels. ID perv: botndary cunution smultions, previre regulation ext be handled
Suailze way, by cing the coordinates uf all atoms 2y i small movi sk eh step, whore tho ealing
foot esomined Ihe alo ofthe current anton pressure the (arg feeure. TA The, Re
ue of (ae watusiaon box sen vary unl ihe appropriate deni is acbueved. Allheugh these procedures
sue au, gvsralved lr desigoed! ta generste populations hat exatly ralch comecational thermndyna mic
eembles, Ibe obser) Aucuations ia terperatuze and pressure Cehich con he siae tor sal
Siutaionapstems} are vlos to those expected forthe vemsearonal exes, and the mapsieations 19
esn's equations ave relively sm eepedilly lor long ceuaaliom lames, Other wanperacurs ah
pressure cegilalion methods are avaiable the SPASMIS progrim,

ho all jalan op jamal mdm ofthe mule dpimik algeria ane pense, The Sse
implements the PEACS sorte, wbich titempts to force the tajctne ta Fills contr af ennstane
potential energy [351 IL be target coniour slowly lowered, this cia be an cote alematise to
‘Smulitee anneal Io find low energy rgons af cunlumatiansl spa. A seme matfestionlaits the
‘solute magnlide ul any component or the velocity al each ep Its cell wal placed well above
the mim portion ut tks Muswell Holtanann veloig dtribatior, andl series (a peewee
Ile SHAK procedure that can occasionally aceur hen integraioa eons alow toa ita approach
c:uh oiker toa che, We dnd eh vlootyiitation precedaze to be bel eLiniaating probes
‘rili SHAKE, postialary when perorming NMIR refinement

Sik NMR based reainte

‘The ways at which eaperimental retrints based on NMA dala ean be ued la generate solution
somuctues b Lupe tp large th Es eaidorod io ny detail hese. bn ation Lo yer eves (54—58]
Several papers have outlined the particular appraach taken im the AMULR oles [57-59] Fer the
Tras! ypes Of Uiktane> and angle coastaiats. wo havo wied co muke the specianiu s flxin 2
posible on 1o make the input as natural a possible for prutcing specteuseopits, SANDER she
Tmvcrporsce some Jestoomuon-uted contrainte, asding time-weriged vistance ari angie ca
Strona penalty functions bated om relaeaton-mati ctimetos of NOLSY interns exon Chemical
shill

5A Bronce and angle peas

“The most sora eppeoach at present ie co nerpne: NOESY sotemies eisnce consents and
covplng oslaabs in isons of ditedral angle eonetrunts. In sander, the veer can deline itl
Festronls un bunds. valence angles. and torions, and che Fores constants und tinge! values for the
Festrl ora vary daring te simulation, Restraints eum alo be amposed dec in terme of Komplete
relations for toon anples [61.2 The penal faneco. can canst of us meny 1 Ute types rg:
con be lat between one set of epost ane wer bounds (alld 7 un 1; ther. se pabulially when
the intemal cuore volun disse hound and tn, since lange woltione any lea Uo eecesire
parabule pemalis, these paratolus cum senoorly turn into Tneas penalties ousie even wider oper al
Tver bouns (elles #1 an 741 The raposiion of teatraints car be oad dependent spun che stn:
Ta estes ae sparta tbe amino-acid sequence, su that mUC of the functionality Of progres ihe
TDISMAN [63 is wanable