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.  We illustrate the method for two compounds of increasing size and complexity : ethanol and 1-naphtol . In each case  we show that convergence of the hydration free energy is achieved rapidly when conventional approaches fail .
We present a family of alchemical perturbation potentials that enable the calculation of hydration free energies 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 alchemical perturbation potentials of this kind. The optimization procedure is based on the \lambda-function formalism and the maximum-likelihood parameter estimation procedure we developed earlier to avoid the occurrence of multi-modal distributions of the coupling energy along the alchemical path. A novel soft-core function applied to the overall solute-solvent interaction energy rather than individual interatomic pair potentials critical for this result is also presented. Because it does not require modifications of core force and energy routines, the soft-core formulation can be easily deployed in molecular dynamics simulation codes. We illustrate the method by applying it to the estimation of the hydration free energy in water droplets of compounds of varying size and complexity . In each case , we show that convergence of the hydration free energy is achieved rapidly . This work paves the way for the ongoing development of more streamlined algorithms to estimate free energies of molecular binding with explicit solvation .
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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
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based on avoiding first order pseudo phase transitions
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A novel soft-core function applied to the overall solute-solvent interaction energy rather than individual interatomic pair potentials critical for this result is also presented. Because it does not require modifications of core force and energy routines, the soft-core formulation can be easily deployed in molecular dynamics simulation codes.
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by applying it to the estimation of the hydration free energy in water droplets of compounds of varying
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: ethanol and 1-naphtol
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. This work paves the way for the ongoing development of more streamlined algorithms to estimate free energies of molecular binding with explicit solvation