Accuracy, precision, and efficiency of nonequilibrium alchemical methods for computing free energies of solvation. I. Bidirectional approaches.

In the context of molecular dynamics simulations, alchemical approaches based on nonequilibrium techniques are recently emerging as a powerful method for the computation of solvation free energy of druglike compounds. Here, we present a rigorous and extensive analysis of the accuracy and precision of the method as a function of the parameters qualifying the nonequilibrium alchemical protocol (e.g., number and length of the nonequilibrium trajectories and decoupling or recoupling alchemical schedule) on a selection of drug-size organic compounds characterized by a nontrivial conformational free energy landscape. The study is organized in two contributions. The first paper includes a detailed description of method and of the conformational behavior of molecular systems. Results are focused on the accuracy and precision bidirectional estimates of solvation free energy, notably those based on the so-called Bennett acceptance ratio. In the second paper, unidirectional estimates for solvation free energy are analyzed in depth.