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Cited by 310Computational Drug Discovery MethodsProtein Structure and DynamicsAdvanced Chemical Physics Studies

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Predicting Absolute Ligand Binding Free Energies to a Simple Model Site

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Mobley, David L., Graves, Alan P., Chodera, John D., McReynolds, Andrea C., Shoichet, Brian K., Dill, Ken A.·2007·Journal of Molecular Biology
DOI 10.1016/j.jmb.2007.06.002PMC PMC2104542
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Abstract

A central challenge in structure-based ligand design is the accurate prediction of binding free energies. Here we apply alchemical free energy calculations in explicit solvent to predict ligand binding in a model cavity in T4 lysozyme. Even in this simple site, there are challenges. We made systematic improvements, beginning with single poses from docking, then including multiple poses, additional protein conformational changes, and using an improved charge model. Computed absolute binding free energies had an RMS error of 1.9 kcal/mol relative to previously determined experimental values. In blind prospective tests, the methods correctly discriminated between several true ligands and decoys in a set of putative binders identified by docking. In these prospective tests, the RMS error in predicted binding free energies relative to those subsequently determined experimentally was only 0.6 kcal/mol. X-ray crystal structures of the new ligands bound in the cavity corresponded closely to predictions from the free energy calculations, but sometimes differed from those predicted by docking. Finally, we examined the impact of holding the protein rigid, as in docking, with a view to learning how approximations made in docking affect accuracy and how they may be improved.

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Metadata

Authors
Mobley, D. L., Graves, A. P., Chodera, J. D., McReynolds, A. C., Shoichet, B. K., & Dill, K. A.
Affiliations
University of California, San Francisco (US)
Corresponding author
  • Shoichet, Brian K.
  • Dill, Ken A.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2007-08
Volume
371
Issue
4
Pages
1118-1134
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2007.06.002
PMC
PMC2104542
OpenAlex
W2128494768
Cited by
310
References
0
Citations by year
2026: 7 · 2025: 9 · 2024: 19 · 2023: 8 · 2022: 21 · 2021: 11 · 2020: 14 · 2019: 10 · 2018: 20 · 2017: 12 · 2016: 21 · 2015: 12 · 2014: 12 · 2013: 19 · 2012: 24
FWCI
23.38
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (GM63592)
  • U.S. Air Force
  • University of California, San Francisco
  • National Institute of General Medical Sciences (R01GM063592, R56GM063592, R01GM034993, GM59957, R01GM059957, GM63592)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
Keywords
absolute binding free energy, alchemical free energy calculations, T4 lysozyme, structure-based ligand design, explicit solvent, protein conformational change, charge model, docking, decoy discrimination, protein-ligand binding
MeSH terms
Binding Sites, Computer Simulation, Ligands, Models, Molecular, Protein Binding, Proteins, Temperature, Titrimetry, Protein Structure, Tertiary, Crystallography, X-Ray, Hydrophobic and Hydrophilic Interactions

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