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On the use of orientational restraints and symmetry corrections in alchemical free energy calculations
Open accessAbstract
Alchemical free energy calculations are becoming a useful tool for calculating absolute binding free energies of small molecule ligands to proteins. Here, we find that the presence of multiple metastable ligand orientations can cause convergence problems when distance restraints alone are used. We demonstrate that the use of orientational restraints can greatly accelerate the convergence of these calculations. However, even with this acceleration, we find that sufficient sampling requires substantially longer simulations than are used in many published protocols. To further accelerate convergence, we introduce a new method of configuration space decomposition by orientation which reduces required simulation lengths by at least a factor of 5 in the cases examined. Our method is easily parallelizable, well suited for cases where a ligand cocrystal structure is not available, and can utilize initial orientations generated by docking packages.
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“In principle, the binding free energy should be independent of the type of restraints, the atom centers selected for the construction of the restraints, or the values of the force constants,64,77,86 provided stable restraints that have been appropriately selected.87”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [86]
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Metadata
- Authors
- Mobley, D. L., Chodera, J. D., & Dill, K. A.
- Affiliations
- University of California, San Francisco (US)
- Venue
- The Journal of Chemical Physics
- Publisher
- AIP Publishing
- Published
- 2006-08-22
- Volume
- 125
- Issue
- 8
- Pages
- 084902-084902
- ISSN
- 0021-9606 (ISSN-L)
- 1089-7690
- PMC
- PMC3583553
- OpenAlex
- W1965762256
- Cited by
- 316
- References
- 50
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 19 · 2023: 18 · 2022: 23 · 2021: 18 · 2020: 18 · 2019: 13 · 2018: 17 · 2017: 15 · 2016: 13 · 2015: 11 · 2014: 17 · 2013: 16 · 2012: 20
- FWCI
- 12.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Chemical Physics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM063592, GM34993, R56GM063592, R01GM034993, GM 063592)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › 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
- alchemical free energy calculations, absolute binding free energy, protein-ligand binding, convergence acceleration
- MeSH terms
- Biophysics, Catechols, Chemistry, Physical, Computer Simulation, Crystallization, Ligands, Models, Chemical, Models, Molecular, Models, Theoretical, Molecular Conformation, Proteins, Software, Thermodynamics, Models, Statistical, Phenol
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