Revisiting Partition in Hydrated Bilayer Systems.

We discuss potential-of-mean force convergence issues involving the methods for generating starting structures of umbrella sampling simulations for the study of the water-bilayer permeation of drug-like compounds. We provide a proof of concept of the benefits of potential-energy modification methods, in particular the flooding technique, to enhance the sampling and improve the convergence of the potential-of-mean force. In addition, we also discuss how these potential modifiers could introduce the necessary bias to induce the correct description of other relevant internal degrees of freedom for the compounds, thus providing a more accurate description of the permeation process. Effective methodological approximations are taken into consideration, more specifically the inclusion of atomic polarization, and experimental data are used in the validation of computed values whenever possible. The parametrization of the atomic point charges is always a relevant issue in biomolecular simulations. We discuss the influence of a molecule's conformation-dependent atomic point charges and their impact on the predicted potential-of-mean force.