Received June 27, 2005

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.

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