Binding Free Energies of Host-Guest Systems by Nonequilibrium Alchemical Simulations with Constrained Dynamics: Illustrative Calculations and Numerical Validation.

In the companion article (Giovannelli et al., 10.1021/acs.jctc.7b00594), we presented an alchemical approach, based on nonequilibrium molecular dynamics simulations, to compute absolute binding free energies of a generic host-guest system. Two alternative computational routes, called binded-domain and single-point alchemical-path schemes, have been proposed. This study is addressed to furnish numerical validation and illustrative examples of the above-mentioned alchemical schemes. Validation is provided by comparing binding free-energy data relative to two poses of a Zn(II)·anion complex with those recovered from an alternative approach, based on steered molecular dynamics simulations. We illustrate important technical and theoretical aspects for a good practice in applying both alchemical schemes, not only through the calculations on the Zn(II)·anion complex, but also estimating absolute binding free energies of 1:1 complexes of β-cyclodextrin with aromatic compounds (benzene and naphthalene). Comparison with experimental data and previous molecular dynamics simulation studies further confirms the validity of the present nonequilibrium-alchemical methodology.