Protein Design Using Continuous Rotamers 英文参考文献.docVIP

ProteinDesignUsingContinuousRotamers PabloGainza1.,KyleE.Roberts1.,BruceR.Donald1,2 * 1DepartmentofComputerScience,DukeUniversity,Durham,NorthCarolina,UnitedStatesofAmerica,2DepartmentofBiochemistry,DukeUniversityMedicalCenter, Durham,NorthCarolina,UnitedStatesofAmerica Abstract Optimizing amino acid conformation and identity is a central problem in computational protein design. Protein design algorithmsmustallowrealisticproteinflexibilitytooccurduringthisoptimization,ortheymayfailtofindthebestsequence with the lowest energy. Most design algorithms implement side-chain flexibility by allowing the side chains to move between a small set of discrete, low-energy states, which we call rigid rotamers. In this work we show that allowing continuous side-chain flexibility (which we call continuous rotamers) greatly improves protein flexibility modeling. We presentalarge-scalestudythatcomparesthesequencesandbestenergyconformationsin69protein-coreredesignsusing arigid-rotamermodelversusacontinuous-rotamermodel.Weshowthatinnearlyallofourredesignsthesequencefound by the continuous-rotamer model is different and has a lower energy than the one found by the rigid-rotamer model. Moreover,thesequencesfoundbythecontinuous-rotamermodelaremoresimilartothenativesequences.Wethenshow thattheseeminglyeasysolutionofsamplingmorerigidrotamerswithinthecontinuousregionisnotapracticalalternative toacontinuous-rotamermodel:atcomputationallyfeasibleresolutions,usingmorerigidrotamerswasneverbetterthana continuous-rotamer model and almost always resulted in higher energies. Finally, we present a new protein design algorithmbasedonthedead-endelimination(DEE)algorithm,whichwecalliMinDEE,thatmakestheuseofcontinuous rotamersfeasibleinlargersystems.iMinDEEguaranteesfindingtheoptimalanswerwhilepruningthesearchspacewith closetothesameefficiencyofDEE.Availability:SoftwareisavailableundertheLesserGNUPublicLicensev3.Contactthe authorsforsourcecode. Citation:GainzaP,RobertsKE,DonaldBR(2012)ProteinDesignUsin