Repulsive Soft-Core Potentials for Efficient Alchemical Free Energy Calculations.

In alchemical free energy (FE) simulations, annihilation and creation of atoms are generally achieved with the soft-core potential that shifts the interparticle separations. While this soft-core potential eliminates the numerical instability occurring near the two end states of the transformation, it makes the hybrid Hamiltonian vary nonlinearly with respect to the parameter λ, which interpolates between the Hamiltonians representing the two end states. This complicates FE estimation by Bennett acceptance ratio (BAR), free energy perturbation (FEP), and thermodynamic integration (TI) methods, thus reducing their calculation efficiency. In this work, we develop a new type of repulsive soft-core potential, called Gaussian soft-core (GSC) potential, with two parameters controlling its maximum and width. The main advantage of this potential is the linearity of the hybrid Hamiltonian with respect to λ, thus permitting the direct application of BAR, FEP, TI, and other variant FE methods. The accuracy and efficiency of the GSC potential are demonstrated by comparing the free energies of annihilation determined for 13 small molecules and an alchemical mutation of a protein side chain. In addition, in combination with a TI integrand (∂H/∂λ) estimation strategy, we show that GSC can considerably reduce the number of λ simulations compared to the commonly used separation-shifted soft-core potential.