Here, we applied alchemical free energy calculations based on molecular simulations to calculating and predicting binding free energies in several different binding sites. We will discuss major challenges facing binding free energy calculations, especially in the form of slow protein and ligand degrees of freedom. Our focus will be on our recent work applying these calculations to binding of trypsin inhibitors, and to blind predictions in another binding site. A significant emphasis will be on the thermodynamic effects of protein conformational changes on binding in these situations. We often find slow motions in proteins, even at the single sidechain level, which contribute multiple kT to binding free energies. Thus, correctly capturing the contributions of these motions to binding proves essential for accuracy in binding prediction.

Small protein conformational changes and their effects on binding thermodynamics

243rd National Meeting (2012)

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