Addressing hysteresis and slow equilibration issues in cavity-based calculation of chemical potentials.

Abstract

In this paper, we explore the strengths and weaknesses of a cavity-based method to calculate the excess chemical potential of a large molecular solute in a dense liquid solvent. Use of the cavity alleviates some technical problems associated with the appearance of (integrable) divergences in the integrand during alchemical particle growth. The excess chemical potential calculated using the cavity-based method should be independent of the cavity attributes. However, the performance of the method (equilibration time and the robustness) does depend on the cavity attributes. To illustrate the importance of a suitable choice of the cavity attributes, we calculate the partition coefficient of pyrene in toluene and heptane using a coarse-grained model. We find that a poor choice for the functional form of the cavity may lead to hysteresis between growth and shrinkage of the cavity. Somewhat unexpectedly, we find that, by allowing the cavity to move as a pseudo-particle within the simulation box, the decay time of fluctuations in the integrand of the thermodynamic integration can be reduced by an order of magnitude, thereby increasing the statistical accuracy of the calculation.