Before revision: We present a family of alchemical perturbation potentials that allow the calculation of hydration free energy of small to medium-sized molecules in a single perturbation step . We also present a general framework to optimize the parameters of the alchemical perturbation potentials based on avoiding first order pseudo phase transitions along the alchemical path.
After revision: We present a family of alchemical perturbation potentials that allow the calculation of hydration free energy of small to medium-sized molecules in a concerted single alchemical coupling step instead of the commonly used sequence of two distinct coupling steps for Lennard-Jones and electrostatic interactions. The perturbation potentials are based on the softplus function of the solute-solvent interaction energy designed to focus sampling near entropic bottlenecks along the alchemical pathway. We present a general framework to optimize the parameters of the alchemical perturbation potentials based on avoiding first order pseudo phase transitions along the alchemical path.