Net charge changes in the calculation of relative ligand-binding free energies via classical atomistic molecular dynamics simulation

The calculation of binding free energies of charged species to a target molecule is a frequently encountered problem in molecular dynamics studies of (bio‐)chemical thermodynamics. Many important endogenous receptor‐binding molecules, enzyme substrates, or drug molecules have a nonzero net charge. Absolute binding free energies, as well as binding free energies relative to another molecule with a different net charge will be affected by artifacts due to the used effective electrostatic interaction function and associated parameters (e.g., size of the computational box). In the present study, charging contributions to binding free energies of small oligoatomic ions to a series of model host cavities functionalized with different chemical groups are calculated with classical atomistic molecular dynamics simulation. Electrostatic interactions are treated using a lattice‐summation scheme or a cutoff‐truncation scheme with Barker–Watts reaction‐field correction, and the simulations are conducted in boxes of different edge lengths. It is illustrated that the charging free energies of the guest molecules in water and in the host strongly depend on the applied methodology and that neglect of correction terms for the artifacts introduced by the finite size of the simulated system and the use of an effective electrostatic interaction function considerably impairs the thermodynamic interpretation of guest‐host interactions. Application of correction terms for the various artifacts yields consistent results for the charging contribution to binding free energies and is thus a prerequisite for the valid interpretation or prediction of experimental data via molecular dynamics simulation. Analysis and correction of electrostatic artifacts according to the scheme proposed in the present study should therefore be considered an integral part of careful free‐energy calculation studies if changes in the net charge are involved. © 2013 The Authors Journal of Computational Chemistry Published by Wiley Periodicals, Inc.