In most protein-ligand binding free energy calculations, both binding partners are flexible. The requirement of full system flexibility incurs considerable computational expense and scales poorly with increasing protein size. I recently derived a theory showing that standard binding free energies may be obtained as an exponential average of the binding potential of mean force (BPMF) - a binding free energy between a ligand and a rigid protein conformation - over the apo ensemble. A BPMF estimation method based on Hamiltonian replica exchange was implemented and tested on the Astex Diverse Set. Precise BPMF estimates were obtained for a large fraction of complexes. In addition, BPMFs were estimated for a subset of the Directory of Useful Decoys. For most tested systems, BPMFs were found to improve binding classification over molecular docking scores.

Absolute binding free energies between ligands and rigid protein conformations: Precise estimation and improved activity classification

250th National Meeting (2015)

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