Recognition of chemical drugs and proteins is important in drug discovery. Accurate free-energy calculations provide mechanistic insights into molecular recognition and conformational equilibrium. We applied an exciting end-point approach to estimating the binding free energies of ligand-protein systems. This approach uses an empirical force field and implicit solvent models, treats the protein binding site as fully flexible, and estimates free energies as sums over local energy wells. The calculations are found to yield encouraging agreement with experimental results for HIV-1 protease inhibitors and protein Kinase inhibitors. The calculations revealed multiple stable, complex conformations and changes in protein and inhibitor conformations, as well as balance in several energetic terms and configurational entropy loss. The results provide relevant physics that can aid in designing inhibitors and understanding protein conformational equilibrium.

Modeling molecular recognition: Free energy calculations for ligand-protein binding

251st National Meeting (2016)

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