A Force Field with Discrete Displaceable Waters and Desolvation Entropy for Hydrated Ligand Docking
Open accessAbstract
In modeling ligand-protein interactions, the representation and role of water are of great importance. We introduce a force field and hydration docking method that enables the automated prediction of waters mediating the binding of ligands with target proteins. The method presumes no prior knowledge of the apo or holo protein hydration state and is potentially useful in the process of structure-based drug discovery. The hydration force field accounts for the entropic and enthalpic contributions of discrete waters to ligand binding, improving energy estimation accuracy and docking performance. The force field has been calibrated and validated on a total of 417 complexes (197 training set; 220 test set), then tested in cross-docking experiments, for a total of 1649 ligand-protein complexes evaluated. The method is computationally efficient and was used to model up to 35 waters during docking. The method was implemented and tested using unaltered AutoDock4 with new force field tables.
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Dockings using the hydrated ligand protocol consistently predicted that waters would be displaced.
“In fact, dockings performed with the hydrated ligand protocol30 consistently predicted the displacement of the waters.”
From AutoDock4<sub>Zn</sub>: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins (2014) · cites this paper as [30]
The Results and discussion > Case studies passage reports that hydrated docking predicted displacement of water A for one ligand and conserved water B. It supports the protocol's ability to predict displacement, but not that its dockings consistently predicted displacement of the waters; the paper says the outcome depends on the ligand. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn AutoDock4, explicit water molecules of the first hydration shell are represented as uncharged spheres directly attached to the ligand, whereas a hydration force field accounting for entropic and enthalpic contributions automatically predicts their potential in mediating protein-ligand interactions.
“In AutoDock4, explicit water molecules of the first hydration shell as represented as uncharged spheres directly attached to the ligand, whereas a hydration force field accounting for the entropic and enthalpic contributions, automatically predicts their potential in mediating protein–ligand interactions (Forli and Olson, 2012).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Forli and Olson, 2012
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Retracted
- Authors
- Forli, S., & Olson, A. J.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Olson, Arthur J.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-01-13
- Volume
- 55
- Issue
- 2
- Pages
- 623-638
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC3319101
- OpenAlex
- W1997409847
- Cited by
- 290
- References
- 69
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 33 · 2023: 24 · 2022: 29 · 2021: 33 · 2020: 22 · 2019: 21 · 2018: 16 · 2017: 11 · 2016: 14 · 2015: 12 · 2014: 9 · 2013: 8 · 2012: 5
- FWCI
- 6.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (R01 GMO69832)
- National Institute of General Medical Sciences (R01GM069832)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › 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
- protein-ligand docking, structure-based drug design, force field calibration
- MeSH terms
- Binding Sites, Computer Simulation, Ligands, Models, Molecular, Proteins, Water, Molecular Structure, Crystallography, X-Ray, Entropy, Coordination Complexes
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