Accelerating Replica Exchange Molecular Dynamics: A Comparison of Hydrogen Mass Repartitioning and Light Water Models

Accelerating conformational sampling through changes in molecular mass is an attractive option in biomolecular modeling. Here, we examine the utility and compare the efficiency of hydrogen mass repartitioning (HMR) and light water (LW) models in the context of replica exchange (RE) simulations of an alanine dipeptide. To maintain integrator stability, we introduced scaling of integration steps with RE temperatures and determined their maximum values, assuring the stability of RE simulations. HMR2 and HMR3 models featuring doubled and tripled hydrogen masses and, to a lesser extent, the LW model reproduce the energetic and conformational properties of alanine dipeptide in water compared to the HMR1 reference. This conclusion is based on comparing kinetic and potential energies, free energy landscapes of the peptide, as well as its structural properties, including hydrogen bonding, water counts in the peptide first solvation shell, and RMSD distributions. Thereby, our results demonstrate that both HMR and LW models can be integrated into RE simulations. We then compared HMR and LW models with respect to the computational efforts required to equilibrate alanine dipeptide. HMR2 and HMR3 are up to 4-fold more computationally efficient than the HMR1 reference, whereas LW lags behind being less than a factor of 2 more efficient. As a result, LW efficiency is 2-fold lower than that of HMR3. This outcome means that increasing the integration step provides faster sampling than boosting water diffusion. Even if the computation of long-range interactions is adjusted with the length of the integration step and the step in LW simulations is further increased, the model remains less efficient than HMR3. We considered a hybrid variant of LW, hLW, featuring heavier water and mass repartitioning applied to all hydrogens, affording longer integration steps than LW does. hLW improves computational efficiency and provides more accurate reproduction of energetic and conformational properties of alanine dipeptide than LW. We concluded that HMR3 and hLW models demonstrate good performance in replica exchange simulation, but the former is preferable due to broader applicability and simplicity. hLW remains an excellent alternative to HMR3, but its scope is limited to "water-rich" systems. More generally, our findings suggest that among the two approaches, HMR or decreasing water mass, the former is more effective. Since LW simulations are not currently supported out-of-the-box by the NAMD molecular dynamics program, we implemented a patch enabling LW functionality.