Alchemical transformations for concerted hydration free energy estimation with explicit solvation

We present a family of alchemical perturbation potentials that enable the calculation hydration free energies small to medium-sized molecules in concerted single coupling step instead commonly used sequence two distinct steps for Lennard-Jones and electrostatic interactions. The are based on softplus function solute-solvent interaction energy designed focus sampling near entropic bottlenecks along pathway. general framework optimize parameters this kind. optimization procedure is $\lambda$-function formalism maximum-likelihood parameter estimation we developed earlier avoid occurrence multi-modal distributions path. A novel soft-core applied overall rather than individual interatomic pair critical result also presented. Because it does not require modifications core force routines, formulation can be easily deployed molecular dynamics simulation codes. illustrate method by applying water droplets compounds varying size complexity. In each case, show convergence achieved rapidly. This work paves way ongoing development more streamlined algorithms estimate binding with explicit solvation.