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

Duboué-Dijon, E.; Hénin, J.

doi:10.1063/5.0046853

Cited by 46Computational Drug Discovery MethodsAdvanced Physical and Chemical Molecular InteractionsProtein Structure and Dynamics

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

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Duboué-Dijon, E., Hénin, J.·2021·The Journal of Chemical Physics

DOI 10.1063/5.0046853

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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.

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While the path-based PMF approach appears more tractable, it is still difficult to obtain converged free energy estimates for large biomolecules with complex geometries.
“While the path-based PMF approach appears more tractable, it is still difficult to obtain converged free energy estimates for large biomolecules with complex geometries.53,62−68”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [63]
More precise free energy changes can be obtained through the application of restraints which ensure that the relative orientation and position of the ligand with respect to the receptor is preserved and therefore the available phase space to be sampled during the simulations is reduced.
“More precise free energy changes can be obtained through the application of restraints which ensure that the relative orientation and position of the ligand with respect to the receptor is preserved and therefore the available phase space to be sampled during the simulations is reduced.54,63−65”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [63]
Since the coiled coils in the present study are all homomultimers composed of identical α-helical monomers, the effect of symmetry must be considered during the calculation of the binding free energy, and a symmetry correction must be applied.
“Since the coiled coils in the present study are all homomultimers composed of identical α-helical monomers, the effect of symmetry must also be considered during the calculation of the binding free energy.63,69 Therefore, a symmetry correction must be applied to the binding free energy as follows”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [63]

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Publisher’s Note: “Building intuition for binding free energy calculations: Bound state definition, restraints, and symmetry” [J. Chem. Phys. 154, 204101 (2021)]
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Authors: Duboué-Dijon, E., & Hénin, J.
Affiliations: CNRS, Université de Paris, UPR 9080, Laboratoire de Biochimie Théorique 1 , 13 rue Pierre et Marie Curie, 75005 Paris, France
Centre National de la Recherche Scientifique (FR)
Corresponding author: Hénin, J.
ORCID: Duboué-Dijon, E.
Hénin, J.
Venue: The Journal of Chemical Physics
Publisher: AIP Publishing
Published: 2021-05-24
Volume: 154
Issue: 20
Pages: 204101-204101
ISSN: 0021-9606 (ISSN-L)
1089-7690
DOI: 10.1063/5.0046853
OpenAlex: W3127325433
Cited by: 46
References: 81
Citations by year: 2026: 4 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 17 · 2021: 2
FWCI: 4.61
Type: journal article
Language: en
Update notices: correction (2021-06-09)
Open access: green
arxiv.org
Locations: The Journal of Chemical Physics (publishedVersion)
PubMed (publishedVersion)
arXiv (Cornell University) (submittedVersion)
HAL (submittedVersion, other-oa)
arXiv (Cornell University)
Funders: Agence Nationale de la Recherche (ANR-11-LABX-0011, ANR-11-EQPX-0008)
Topics: Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords: absolute binding free energy, binding sites, homodimerization, conformational sampling

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

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