Assessment of Binding Affinity via Alchemical Free-Energy Calculations
Open accessPublished version of a preprint
Abstract
Free-energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free-energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace, and OpenMM and uses the AMBER 14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset, the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall’s τ was 0.53 ± 0.05, which are broadly comparable to or better than previously reported results using other methods.
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More rigorous free energy methods such as alchemical binding free energy calculations have become established for the computation of binding free energies of small molecules to proteins with MD.
“More rigorous free energy methods such as alchemical binding free energy calculations have become established for the computation of binding free energies of small molecules to proteins with MD.55−60”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [60]
Cites
Using AMBER18 for Relative Free Energy Calculations
Song, L. F., Lee, T.-S., Zhu, C., York, D. M., & Merz, K. M. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.9b00105 · Cited by 234 · see citing works
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The maximal and current accuracy of rigorous protein-ligand binding free energy calculations
Ross, G. A., Lu, C., Scarabelli, G., Albanese, S. K., Houang, E., Abel, R., Harder, E. D., & Wang, L. (2023) · Communications Chemistry · doi:10.1038/s42004-023-01019-9 · Cited by 178 · see citing works
Notari, E., Wood, C. W., & Michel, J. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.4c01695 · Cited by 4 · see citing works
Self-citation
- Authors
- Kuhn, M., Firth-Clark, S., Tosco, P., Mey, A. S. J. S., Mackey, M., & Michel, J.
- Affiliations
- Cresset (United Kingdom) (GB)
- Cresset , New Cambridge House, Bassingbourn Road , , ,
- University of Edinburgh (GB)
- Corresponding author
- Mackey, Mark
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-05-21
- Volume
- 60
- Issue
- 6
- Pages
- 3120-3130
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- OpenAlex
- W3027827456
- Cited by
- 222
- References
- 1
- Citations by year
- 2026: 26 · 2025: 47 · 2024: 31 · 2023: 38 · 2022: 35 · 2021: 29 · 2020: 16
- FWCI
- 14.78
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of Chemical Information and Modeling (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Engineering and Physical Sciences Research Council (EP/P022138/1)
- Innovate UK (011120)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- alchemical free energy calculations, binding affinity prediction, workflow automation, structure-based drug design, protein-ligand binding, sanity checks, sires, OpenMM
- MeSH terms
- Ligands, Protein Binding, Software, Thermodynamics, Drug Design, Reproducibility of Results
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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