Introduction An Algorithm for Computing Nucleic Acid Base-Pairing Probabilities Including P

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AnAlgorithmforComputingNucleicAcidBase-PairingProbabilitiesIncludingPseudoknots

ROBERTM.DIRKS,1NILESA.PIERCE21DepartmentofChemistry,CaliforniaInstituteofTechnology,Pasadena,California91125

2DepartmentsofApplied&ComputationalMathematicsandBioengineering,CaliforniaInstitute

ofTechnology,MailCode114-96,Pasadena,California91125

Received21January2004;Accepted19March2004DOI10.1002/jcc.20057PublishedonlineinWileyInterScience(www.interscience.wiley.com).

Abstract:Givenanucleicacidsequence,arecentalgorithmallowsthecalculationofthepartitionfunctionover

secondarystructurespaceincludingaclassofphysicallyrelevantpseudoknots.Here,wepresentamethodforcomputingbase-pairingprobabilitiesstartingfromtheoutputofthispartitionfunctionalgorithm.Theapproachreliesonthecalculationofrecursionprobabilitiesthatarecomputedbybacktrackingthroughthepartitionfunctionalgorithm,applyingaparticulartransformationateachstep.Thistransformationisapplicabletoanypartitionfunctionalgorithmthatfollowsthesamebasicdynamicprogrammingparadigm.Base-pairingprobabilitiesareusefulforanalyzingtheequilibriumensemblepropertiesofnaturalandengineerednucleicacids,asdemonstratedforahumantelomeraseRNAandasyntheticDNAnanostructure.

©2004WileyPeriodicals,Inc.JComputChem25:1295–1304,2004

Keywords:DNA;RNA;base-pairingprobabilities;partitionfunction;pseudoknots

IntroductionThermodynamicmodelsbasedonnucleicacidsecondarystructureandnearest-neighboridentities1–5underlydynamicprogramming

algorithmsforpredictingtheminimumenergysecondarystruc-ture6–10andcalculatingthepartitionfunctionoversecondary

structurespace.10–12Intheiroriginalforms,thesealgorithmsex-

cludethepossibilityofpseudoknots,abiologicallyrelevantclassofsecondarystructures13thatalsoarisesinDNAnanotechnology

applications.14,15Pseudoknotsresultwhentwobasepairsi⅐jand

d⅐e,withiϽd,failtosatisfythenestingpropertyiϽdϽeϽj(see,e.g.,Fig.1).Recentextensionsofthestructurepredic-tion16–18andpartitionfunction18algorithmsallowtheinclusionof

certainpseudoknots.Foranensembleofsecondarystructuressʦ⍀,thepartitionfunction

Qϭ͸

sʦ⍀eϪGs/RT

maybeusedtocomputetheprobabilityp͑s*͒ϭ1QeϪGs*/RT(1)

thatsecondarystructures*issampledatthermodynamicequilib-rium.Theensembleequilibriumcanalsobecharacterizedbythematrixofbase-pairingprobabilitieswithentriespi,jcorresponding

totheprobabilitythatbaseiispairedwithbasejin⍀.McCaskill’soriginalarticle11defineselegantdynamicpro-

gramstocomputethepartitionfunctionandbase-pairingproba-bilitiesovertheensembleofunpseudoknottedsecondarystruc-tures.Thepartitionfunctionalgorithmbuildsuprecursivelyfromshortsubsequencestothefullstrand,andthenthepairprobabilitiesarecomputedbyworkingbackwardstoshortsubsequencesusingintermediateresultsfromthepartitionfunctioncalculation.Intheabsenceofpseudoknots,thepartitionfunctionalgorithmissuffi-cientlysuccinctthatMcCaskillisabletodeterminetheformofthepairprobabilitybacktrackalgorithmsimplybyconsideringthefewpossibleformsofenclosingsecondarystructureforanygivenbasepair.Althoughthisapproachissimpleandefficient,itisnoteasily

Correspondenceto:NilesA.Pierce;e-mail:niles@caltech.eduContract/grantsponsor:NSFgraduateresearchfellowship(R.M.D.).Contract/grantsponsor:DefenseAdvancedResearchProjectsAgency(DARPA)andAirForceResearchLaboratoryunderF30602-010200561(N.A.P.).

Contract/grantsponsor:RalphM.ParsonsFoundation(N.A.P.).Contract/grantsponsor:CharlesLeePowellFoundation(N.A.P.).

©2004WileyPeriodicals,Inc.generalizabletoalgorithmicextensions,suchastheinclusionofpseudoknots.Here,wedescribeageneralmethodformechanicallytransformingthenewpseudoknotpartitionfunctionalgorithm18to

computerecursionprobabilities,whichcanbeusedinturntocomputebase-pairingprobabilities.Thetransformationapproachisgeneralizabletoanyfuturepartitionfunctionextensionsthatfollowthesamedynamicprogrammingparadigm.Base-pairingprobabilitiesassistintheanalysisofbiologicallyrelevantpseudoknots.Here,weexaminehumantelomeraseRNA,whichexistsatequilibriuminbothhairpinandpseudoknottedforms.19Atwo-pointmutation,implicatedinthediseasedysker-

atosiscongenita,altersthethermodynamicbalancebetweenthesecompetingstructures.20Thisshiftinequilibriumisclearlyidenti-

fiablewhenthebase-pairingprobabilitiesforthetwosequencesarecompared.Base-pairingprobabilitiesthatpermitpseudoknotsarealsousefulinanalyzingsyntheticDNAnanostructures.14,15

AlgorithmForclarity,webeginbyconsideringtheclassofsecondarystruc-turesexcludingpseudoknotsandthenaddresstheadditionalcom-plexitythatariseswhenpseudoknotsareintroduced.