Path Dependence in Alchemical Calculations of Water Chemical Potential in Aqueous Electrolytes

TL;DR

This study reveals that the pathway chosen in alchemical calculations significantly impacts the accuracy of water's chemical potential estimates in aqueous electrolytes, emphasizing the need for careful protocol design.

Contribution

The paper systematically compares different alchemical insertion pathways, highlighting how pathway order affects convergence and chemical plausibility in ionic solutions.

Findings

Concurrent activation of van der Waals and electrostatics can cause implausible free energies.

Activating van der Waals interactions before electrostatics yields more consistent results.

Pathway design critically influences the reliability of free energy calculations in ionic environments.

Abstract

Accurate calculation of free energies and their derivatives is central to assessing the thermodynamic stability of molecular and particulate systems across length scales. Yet such quantities can be difficult to compute reliably in strongly interacting systems, such as solutions of ionic species in polar solvents. One important example is the chemical potential of water in aqueous electrolytes, which can be estimated through staged particle insertion by gradually coupling an inserted molecule to its environment. Although the resulting insertion free energy should be independent of the alchemical pathway, the order and manner in which van der Waals and electrostatic interactions are activated can strongly affect convergence and, in some cases, yield inconsistent estimates. Here, we examine this issue by calculating water's chemical potential in aqueous KCl solutions using eight alchemical insertion pathways that differ in the extent and order of van der Waals and Coulombic coupling. We find that concurrently activating these interactions, particularly in fully coupled and partially end-coupled protocols, can produce chemically implausible insertion free energies. These anomalies arise from intermediate states in which the inserted water molecule develops strong electrostatic interactions with a chloride ion before sufficient short-range repulsion has been established. In contrast, pathways that activate short-range van der Waals interactions before electrostatics yield more consistent and chemically plausible estimates. These findings demonstrate that practical alchemical calculations in polar and ionic environments can be highly sensitive to pathway design, underscoring the importance of decoupling short-range and electrostatic interactions in staged insertion alchemical protocols.