SnugDock Paratope Structural Optimization during Antibody-Antigen Docking Compensates for Errors in Antibody Homology Models 英文参考文献.docVIP

SnugDock:ParatopeStructuralOptimizationduring Antibody-AntigenDockingCompensatesforErrorsin AntibodyHomologyModels AroopSircar1,JeffreyJ.Gray1,2* 1ChemicalBiomolecularEngineering,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica,2PrograminMolecularComputationalBiophysics, JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica Abstract High resolution structures of antibody-antigen complexes are useful for analyzing the binding interface and to make rationalchoicesforantibodyengineering.Whenacrystallographicstructureofacomplexisunavailable,thestructuremust be predictedusingcomputational tools.Inthis work,weillustrate anovel approach, namedSnugDock,topredicthigh- resolutionantibody-antigencomplexstructuresbysimultaneouslystructurallyoptimizingtheantibody-antigenrigid-body positions,therelativeorientationoftheantibodylightandheavychains,andtheconformationsofthesixcomplementarity determining region loops. This approach is especially useful when the crystal structure of the antibody is not available, requiring allowances for inaccuracies in an antibody homology model which would otherwise frustrate rigid-backbone dockingpredictions.LocaldockingusingSnugDockwiththelowest-energyRosettaAntibodyhomologymodelproduced moreaccuratepredictionsthanstandardrigid-bodydocking.SnugDockcanbecombinedwithensembledockingtomimic conformer selection and induced fit resulting in increased sampling of diverse antibody conformations. The combined algorithm produced four medium (Critical Assessment of PRediction of Interactions-CAPRI rating) and seven acceptable lowest-interface-energy predictions in a test set of fifteen complexes. Structural analysis shows that diverse paratope conformations are sampled, but docked paratope backbones are not necessarily closer to the crystal structure conformationsthanthestartinghomologymodels.TheaccuracyofSnugDockpredictionssuggestsanewgenreofgeneral docking algorithms with flexible binding interfaces targeted towards making homo