title: Absolute FKBP binding affinities obtained via nonequilibrium unbinding simulations.
abstract: We compute the absolute binding affinities for two ligands bound to the FKBP protein using nonequilibrium unbinding simulations. The methodology is straightforward requiring little or no modification to many modern molecular simulation packages. The approach makes use of a physical pathway, eliminating the need for complicated alchemical decoupling schemes. We compare our nonequilibrium results to those obtained via a fully equilibrium approach and to experiment. The results of this study suggest that to obtain accurate results using nonequilibrium approaches one should use the stiff-spring approximation with the second cumulant expansion. From this study we conclude that nonequilibrium simulation could provide a simple means to estimate protein-ligand binding affinities.
authors.affiliation: Department of Physics, University of Idaho, Moscow, Idaho 83844-0903, USA. ytreberg@uidaho.edu
authors.forename: F Marty
authors.initials: FM
authors.lastname: Ytreberg
mesh_terms: D000093:Acetoin / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D004121:Dimethyl Sulfoxide / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D000093:Acetoin; D022021:Tacrolimus Binding Proteins; D004121:Dimethyl Sulfoxide