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Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design
Open accessAbstract
Recent calorimetric studies of interactions between small molecules and biomolecular targets have generated renewed interest in the phenomenon of entropy-enthalpy compensation. In these studies, entropic and enthalpic contributions to binding are observed to vary substantially and in an opposing manner as the ligand or protein is modified, whereas the binding free energy varies little. In severe examples, engineered enthalpic gains can lead to completely compensating entropic penalties, frustrating ligand design. Here, we examine the evidence for compensation, as well as its potential origins, prevalence, severity, and ramifications for ligand engineering. We find the evidence for severe compensation to be weak in light of the large magnitude of and correlation between errors in experimental measurements of entropic and enthalpic contributions to binding, though a limited form of compensation may be common. Given the difficulty of predicting or measuring entropic and enthalpic changes to useful precision, or using this information in design, we recommend ligand engineering efforts instead focus on computational and experimental methodologies to directly assess changes in binding free energy.
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“While the path-based PMF approach appears more tractable, it is still difficult to obtain converged free energy estimates for large biomolecules with complex geometries.53,62−68”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [66]
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Metadata
- Authors
- Chodera, J. D., & Mobley, D. L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Irvine (US)
- Venue
- Annual Review of Biophysics
- Publisher
- Annual Reviews
- Published
- 2013-05-06
- Volume
- 42
- Issue
- 1
- Pages
- 121-142
- ISSN
- 1936-122X (ISSN-L)
- 1936-1238
- PMC
- PMC4124006
- OpenAlex
- W2151022427
- Cited by
- 531
- References
- 119
- Citations by year
- 2026: 43 · 2025: 43 · 2024: 35 · 2023: 42 · 2022: 45 · 2021: 42 · 2020: 35 · 2019: 38 · 2018: 36 · 2017: 46 · 2016: 42 · 2015: 46 · 2014: 30 · 2013: 7
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1r15gm096257-01a1)
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (1R15GM096257-01A1, R15 GM096257)
- Topics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- enthalpy-entropy compensation, binding free energy, ligand design, ligand recognition, protein-ligand interactions, calorimetry, binding thermodynamics, ligand engineering
- MeSH terms
- Calorimetry, Ligands, Protein Binding, Proteins, Thermodynamics, Entropy
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