Electrostatic free energy calculations for macromolecules: A hybrid molecular dynamics/continuum electrostatics approach

A hybrid molecular dynamics/continuum electrostatics method is proposed for free energy calculations that involve the creation or deletion of net char ges in a solvated macromolecule, which extends and simplifies an earlier me thod. A limited, spherical region of interest is treated microscopically; t he remainder of the system is treated as a heterogeneous dielectric continu um. The spherical region contains part of the macromolecule and a limited n umber of explicit solvent molecules, while the outer region contains the re mainder of the macromolecule and bulk solvent. In a first step, the dielect ric constant of the macromolecule in the outer region is changed from a val ue typical of the macromolecule (similar to 1-4 for a protein) to a value t ypical of a bulk solvent. Second, the mutation is introduced with a molecul ar dynamics simulation for the spherical region, including the reaction fie ld due to the now-homogeneous outer region, for which analytical expression s are available. Third, the outer macromolecular dielectric constant is cha nged back to its original value. The free energies for steps one and three are obtained from continuum electrostatics. The method is used to calculate the free energy to mutate a negatively charged aspartate ligand into a neu tral asparagine in the active site of aspartyl-tRNA synthetase and shown th rough comparison to the earlier method to be efficient and accurate.