Staging Is More Important than Perturbation Method for Computation of Enthalpy and Entropy Changes in Complex Systems

Abstract

Entropy and enthalpy compensation are frequently observed in thermodynamic measurements. To understand the molecular details of these compensating changes, molecular dynamics or Monte Carlo methods may, in principle, be used. Yet, in practice, computational methods to evaluate changes in entropy and enthalpy usually have much greater (e.g. order of magnitude worse) error than relative free energy calculations. In this paper, we examine ways to improve the computational ability to determine changes in both enthalpy and entropy. Toward that end we consider five different perturbation schemes for enthalpy determination and also consider the relative importance of staging the computation (i.e., dividing the entire perturbation calculation into a series of consecutive smaller ones) along the reaction coordinate. Two model systems are used for evaluation: a system of Lennard-Jones spheres, where the computation is directed to the addition/deletion of a sphere, and the alchemical transformation of an anion in e...