Calculation of absolute binding free energies for charged ligands and effects of long-range electrostatic interactions

A recently proposed molecular dynamics method for estimating binding free energies is applied to the complexation of two charged benzamidine inhibitors with trypsin. The difficulties with calculations of absolute binding energies for charged molecules, associated with long-range electrostatic contributions, are discussed and it is shown how to deal with these effectively. In particular, energetic effects caused by the trunction of dipole-dipole interactions in the medium surrounding the charged ligand are examined and found to be significant. Calculations of the absolute binding energy for benzamidine using the free energy perturbation approach are also reported. These simulations illustrate the typical problems associated with annihilation transformations of molecules bound inside proteins. © 1996 by John Wiley & Sons, Inc.