Molecular Dynamics with Very Large Time Steps for the Calculation of Solvation Free Energies

In multiple time scale molecular dynamics, the use of isokinetic constraints along with massive thermostatting has enabled the adoption of very large integration steps, well beyond the limits imposed by resonance artifacts in standard algorithms. In this work, we present two new contributions to this topic. First, we investigate the velocity distribution and the temperature-kinetic energy relationship associated with the isokinetic Nosé-Hoover family of methods, showing how they depend on the number of thermostats attached to each atomic degree of freedom. Second, we investigate the performance of these methods in the calculation of solvation free energies, the determination of which is often key for understanding the partition of a chemical species among distinct environments. We show how one can extract this property from canonical (constant-NVT) simulations and compare the result to experimental data obtained at a specific pressure. Finally, we demonstrate that large time steps can, in fact, be used to improve the efficiency of these calculations and that attaching multiple thermostats per degree of freedom is beneficial for effectively exploring the configurational space of a molecular system.