Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins Computational techniques see widespread use in pharmaceutical drug discovery, but typically prove unreliable in predicting trends in protein-ligand binding. Alchemical free energy calculations seek to change that by providing rigorous binding free energies from molecular simulations. Given adequate sampling and an accurate enough force field, these techniques yield accurate free energy estimates. Recent innovations in alchemical techniques have sparked a resurgence of interest in these calculations. Still, many obstacles stand in the way of their routine application in a drug discovery context, including the one we focus on here, sampling. Sampling of binding modes poses a particular challenge as binding modes are often separated by large energy barriers, leading to slow transitions. Binding modes are difficult to predict, and in some cases multiple binding modes may contribute to binding. In view of these hurdles, we present a framework for dealing carefully with uncertainty in binding mode or conformation in the context of free energy calculations. With careful sampling, free energy techniques show considerable promise for aiding drug discovery.

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We present a molecular model for studying the prototypical ferric–ferrous electron transfer process in liquid water, and we discuss its structural implications. Treatment of the nonequilibrium dynamics will be the subject of future work. The elementary constituents in the model are classical water molecules, classical ferric ions (i.e., Fe3+ particles), and a quantal electron. Pair potentials and pseudopotentials describing the interactions between these constituents are presented. These interactions lead to ligand structures of the ferric and ferrous ions that are in good agreement with those observed in nature. The validity of the tight binding model is examined. With umbrella sampling, we have computed the diabatic free energy of activation for electron transfer. The number obtained, roughly 20 kcal/mol, is in reasonable accord with the aqueous ferric–ferrous transfer activation energy of about 15 to 20 kcal/mol estimated from experiment. The Marcus relation for intersecting parabolic diabatic free energy surfaces is found to be quantitatively accurate in our model. Due to its significance to future dynamical studies, we have computed the tunnel splitting for our model in the absence of water molecules. Its value is about 1 kB T at room temperature for ferrous–ferric separations around 5.5 Å. This indicates that the dynamics of the electron transfer are complex involving both classical adiabatic dynamics and quantal nonadiabatic transitions. The dynamics may also be complicated due to glassy behavior of tightly bound ligand water molecules. We discuss this glassy behavior and also describe contributions to the solvation energetics from water molecules in different solvation shells. Finally, the energetics associated with truncating long ranged forces is discussed and analyzed.

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