Hydration of amino acid side chains: Nonpolar and electrostatic contributions calculated from staged molecular dynamics free energy simulations with explicit water molecules

A staged protocol for performing molecular dynamics solvation free energy simulations is described. The solvation free energy is expressed in terms of nonpolar and electrostatic contributions, and the nonpolar contribution is further decomposed into repulsive and dispersive contributions using the Weeks, Chandler, and Andersen (WCA) scheme of separating the repulsive and attractive parts in the Lennard-Jones potential. To achieve precise and stable results in the free energy perturbation simulations, the contribution to the free energy from the repulsive part of the potential is computed in multiple stages via a soft-core transformation, whereas a linear coupling scheme is used for both the electrostatic and dispersive contributions. To reduce the computational effort, the free energy simulations are carried out with a small number of explicit solvent water molecules near the solute, whereas the influence of the remaining bulk solvent is represented implicitly in terms of an effective solvent boundary potential. The protocol is used to calculate the hydration free energy of amino acid side chains. Because all of the sampling windows are generated independently of one another, the calculations can all be performed simultaneously in parallel on a computer cluster. The agreement with experimental values and with the high precision computational results of Shirts et al. [J. Chem. Phys. 2003, 119, 5740] shows that this computationally inexpensive protocol is efficient.