New strategies to incorporate the solvent polarization in self‐consistent reaction field and free‐energy perturbation simulations

A first‐order perturbation treatment of the polarization contribution to the free energy of hydration is presented. Very simple expressions for the computation of the total electrostatic free energy of solvation, the polarization contribution, and its components (distortion and stabilization) are derived. These equations can be used with either continuum (quantum and classical) or discrete approaches. The reliability of these equations is examined by comparison with rigorous expressions derived previously within the framework of the self‐consistent reaction field theory. Indeed, the suitability of the classical expressions for the distortion and stabilization terms used in the context of discrete strategies has been explored by comparison between self‐consistent reaction field and molecular dynamics–free‐energy perturbation results. The excellent agreement found between the two techniques allows us to envisage a procedure to account for the polarization in force field‐derived methods.

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