Predicting binding free energies in solution

TL;DR

This paper reviews various factors affecting the accuracy of computational predictions of absolute binding free energies in aqueous solutions, highlighting sources of errors and potential improvements.

Contribution

It summarizes key factors influencing binding free energy calculations and discusses their impact on prediction accuracy in electronic structure theory.

Findings

Multiple factors contribute 1-3 kcal/mol errors at 298 K.

Explicit solvent and conformational sampling are critical for accuracy.

Errors vary across different systems and conditions.

Abstract

Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic for others. In paper I summarize some of the many factors that could easily contribute 1-3 kcal/mol errors at 298 K: three-body dispersion effects, molecular symmetry, anharmonicity, spurious imaginary frequencies, insufficient conformational sampling, wrong or changing ionization states, errors in the solvation free energy of ions, and explicit solvent (and ion) effects that are not well-represented by continuum models. While I focus on binding free energies in aqueous solution the approach also applies (with minor adjustments) to any free energy difference such as conformational or reaction free energy differences or activation free energies in any solvent.