Improved precision and efficiency of free energy calculations for small systems using lambda-scaled atomic masses and separating conformational and transformational sampling

We present results showing the importance of appropriate treatment of atomic masses in molecular dynamics (MD)-based single topology free-energy perturbations (FEPs) on small molecule systems. The reversibility of gas phase simulations is significantly improved by scaling the atomic mass of mutated atoms with the lambda variable normally used for the scaling of energy terms. Because this effect is less pronounced for solvated systems, it will not cancel in estimates of the relative hydration free energy difference. The advantage of mass scaling is demonstrated by a null mutation of ethane to ethane and the calculation of the relative hydration free energy difference between ethane and n-propane. Furthermore, it is found that the simulation time necessary for converged MD/FEPs is prohibitively large for relative hydration free energy calculations on cyclic alkanes. Therefore, we explore an alternative free energy pathway including strongly constrained conformations to improve convergence in FEP simulations of flexible molecules.