Binding enthalpy calculations for a neutral host-guest pair yield widely divergent salt effects across water models

Dissolved salts are a part of the physiological milieu and can significantly influence the kinetics and thermodynamics of various biomolecular processes, such as binding and catalysis; thus, it is important for molecular simulations to reliably describe their effects. The present study uses a simple, nonionized host-guest model system to study the sensitivity of computed binding enthalpies to the choice of water and salt models. Molecular dynamics simulations of a cucurbit[7]uril host with a neutral guest molecule show striking differences in the salt dependency of the binding enthalpy across four water models, TIP3P, SPC/E, TIP4P-Ew, and OPC, with additional sensitivity to the choice of parameters for sodium and chloride. In particular, although all of the models predict that binding will be less exothermic with increasing NaCl concentration, the strength of this effect varies by 7 kcal/mol across models. The differences appear to result primarily from differences in the number of sodium ions displaced from the host upon binding the guest rather than from differences in the enthalpy associated with this displacement, and it is the electrostatic energy that contributes most to the changes in enthalpy with increasing salt concentration. That a high sensitivity of salt affecting the choice of water model, as observed for the present host-guest system despite it being nonionized, raises issues regarding the selection and adjustment of water models for use with biological macromolecules, especially as these typically possess multiple ionized groups that can interact relatively strongly with ions in solution.