Cited by 534thermodynamics and calorimetric analysesProtein Interaction Studies and Fluorescence AnalysisComputational Drug Discovery Methods

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Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

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Chodera, John D., Mobley, David L.·2013·Annual Review of Biophysics

DOI 10.1146/annurev-biophys-083012-130318PMC PMC4124006

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Abstract

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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Authors: Chodera, J. D., & Mobley, D. L.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
University of California, Irvine (US)
ORCID: Chodera, John D.
Mobley, David L.
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
DOI: 10.1146/annurev-biophys-083012-130318
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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Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

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