A new method for carrying out free energy perturbation calculations: Dynamically modified windows

Abstract

A new methodology for carrying out free energy perturbation calculations is derived and implemented in an extensively modified version of the amber 3.0 program (U. C. Singh, P. K. Weiner, J. W. Caldwell, and P. A. Kollman, Department of Pharmaceutical Chemistry, University of California, San Francisco, 1986). In this method, the local slope of the accumulated free energy vs λ curve is used to choose the width, δλ of the next window. This method has been evaluated on several test cases: the free energies of solvation for the noble gases neon, krypton, and xenon; and the free energy of solvation of methane. In each case, good agreement between theory and experiment is obtained in a reasonably short amount of simulation time using the new methodology. In contrast, when these test cases are run using a standard fixed δλ methodology for the same lengths of time, much worse results are obtained. This attests to the ability of the new method to reduce the radius of convergence for these types of free energy calculations.