Efficiency of alchemical free energy simulations. II. Improvements for thermodynamic integration

Abstract

We attempt to optimize the efficiency of thermodynamic integration, as defined by the minimal number of unphysical intermediate states required for the computation of accurate and precise free energy differences. The suitability of various numerical quadrature methods is tested. In particular, we compare the trapezoidal rule, Simpson's rule, Gauss-Legendre, Gauss-Kronrod-Patterson, and Clenshaw-Curtis integration, as well as integration based on a cubic spline approximation of the integrand. We find that Simpson's rule and spline integration are already significantly more efficient that the trapezoidal rule, i.e., correct free energy differences can be obtained using fewer λ-states. We demonstrate that Simpson's rule can be used advantageously with nonequidistant values of the abscissa, which increases the flexibility of the method. Efficiency is enhanced even further if higher order methods, such as Gauss-Legendre, Gauss-Kronrod-Patterson, or Clenshaw-Curtis integration, are used; no more than seven λ-states, which in the case of Clenshaw-Curtis integration include the physical end states, were required for accurate results in all test problems studied. Thus, the performance of thermodynamic integration can equal that of Bennett's acceptance ratio method. We also show, however, that the high efficiency found here relies on the particular functional form of the soft-core potential used; overall, thermodynamic integration is more susceptible to the details of the hybrid Hamiltonian used than Bennett's acceptance ratio method. Therefore, we recommend Bennett's acceptance ratio method as the most robust method to compute alchemical free energy differences; nevertheless, scenarios when thermodynamic integration may be preferable are discussed.