Free enthalpies of replacing water molecules in protein binding pockets.
Open accessAbstract
Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate the displacement of water molecules by an apolar probe in the binding pocket of two proteins, cyclin-dependent kinase 2 and tRNA-guanine transglycosylase, using the method of enveloping distribution sampling (EDS) to obtain free enthalpy differences. In both cases, a ligand core is placed inside the respective pocket and the remaining water molecules are converted to apolar probes, both individually and in pairs. The free enthalpy difference between a water molecule and a CH(3) group at the same location in the pocket in comparison to their presence in bulk solution calculated from EDS molecular dynamics simulations corresponds to the binding free enthalpy of CH(3) at this location. From the free enthalpy difference and the enthalpy difference, the entropic contribution of the displacement can be obtained too. The overlay of the resulting occupancy volumes of the water molecules with crystal structures of analogous ligands shows qualitative correlation between experimentally measured inhibition constants and the calculated free enthalpy differences. Thus, such an EDS analysis of the water molecules in the binding pocket may give valuable insight for potency optimization in drug design.
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The correct prediction of the free energy of binding associated with the ligand displacement of water molecules is a key challenge for currently available docking scoring functions.
“The correct prediction of the free energy of binding associated to the ligand displacement of water molecules is a key challenge for the currently available docking scoring functions (Riniker et al., 2012; Spyrakis and Cavasotto, 2015; Bodnarchuk, 2016).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Riniker et al., 2012
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- Authors
- Riniker, S., Barandun, L. J., Diederich, F., Krämer, O., Steffen, A., & van Gunsteren, W. F.
- Affiliations
- ETH Zurich (CH)
- Boehringer Ingelheim (Germany) (DE)
- Venue
- Journal of Computer-Aided Molecular Design
- Published
- 2012-12
- Volume
- 26
- Issue
- 12
- Pages
- 1293-1309
- ISSN
- 0920-654X (ISSN-L)
- 1573-4951
- OpenAlex
- W2086308487
- Cited by
- 23
- References
- 49
- Citations by year
- 2026: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 2
- FWCI
- 9.10
- Type
- book chapter
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Journal of Computer-Aided Molecular Design (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, other-oa)
- ETH Zürich Research Collection
- 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 › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
- Keywords
- protein pockets, Gibbs free energy, enthalpy-entropy compensation, CDK2, tRNA-guanine transglycosylase, ligand binding, binding free energy, inhibition constant, drug design
- MeSH terms
- Binding Sites, Hydrogen Bonding, Models, Chemical, Pentosyltransferases, Protein Binding, Thermodynamics, Water, Crystallography, X-Ray, Entropy, Cyclin-Dependent Kinase 2, Molecular Dynamics Simulation
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