Building intuition for binding free energy calculations: bound state definition, restraints, and symmetry

TL;DR

This paper clarifies the complex theory of binding free energy calculations, emphasizing physical intuition, the role of symmetry, and restraint contributions to improve understanding and avoid common misconceptions in molecular simulations.

Contribution

It provides a practical, intuition-based explanation of binding free energy calculations, highlighting the correct treatment of symmetry and restraints, and clarifying common misconceptions.

Findings

Symmetry corrections can be replaced by restraint free energy contributions.

Partial sampling of symmetric modes does not impact free energy calculations.

Clarifies the role of bound state definition in free energy computations.

Abstract

The theory behind computation of absolute binding free energies using explicit-solvent molecular simulations is well-established, yet somewhat complex, with counter-intuitive aspects. This leads to frequent frustration, common misconceptions, and sometimes, erroneous numerical treatment. To improve this, we present the main practically relevant segments of the theory with constant reference to physical intuition. We pinpoint the role of the implicit or explicit definition of the bound state (or the binding site), to make a robust link between an experimental measurement and a computational result. We clarify the role of symmetry, and discuss cases where symmetry number corrections have been misinterpreted. In particular, we argue that symmetry corrections as classically presented are a source of confusion, and could be advantageously replaced by restraint free energy contributions. We establish that contrary to a common intuition, partial or missing sampling of some modes of symmetric bound states does not affect the calculated decoupling free energies. Finally, we review these questions and pitfalls in the context of a few common practical situations: binding to a symmetric receptor (equivalent binding sites), binding of a symmetric ligand (equivalent poses), and formation of a symmetric complex, in the case of homodimerization.