title: Grand canonical Monte Carlo simulation of ligand-protein binding.
abstract: A new application of the grand canonical thermodynamics ensemble to compute ligand-protein binding is described. The described method is sufficiently rapid that it is practical to compute ligand-protein binding free energies for a large number of poses over the entire protein surface, thus identifying multiple putative ligand binding sites. In addition, the method computes binding free energies for a large number of poses. The method is demonstrated by the simulation of two protein-ligand systems, thermolysin and T4 lysozyme, for which there is extensive thermodynamic and crystallographic data for the binding of small, rigid ligands. These low-molecular-weight ligands correspond to the molecular fragments used in computational fragment-based drug design. The simulations correctly identified the experimental binding poses and rank ordered the affinities of ligands in each of these systems.
authors.affiliation: Locus Pharmaceuticals Four Valley Square, Blue Bell, Pennsylvania 19422, USA. mclark@locuspharma.com
authors.forename: Matthew
authors.initials: M
authors.lastname: Clark
authors.forename: Frank
authors.initials: F
authors.lastname: Guarnieri
authors.forename: Igor
authors.initials: I
authors.lastname: Shkurko
authors.forename: Jeff
authors.initials: J
authors.lastname: Wiseman
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D009010:Monte Carlo Method; D009113:Muramidase / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013820:Thermolysin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D009113:Muramidase; D013820:Thermolysin