Journal
ANNUAL REVIEW OF BIOPHYSICS, VOL 42
Volume 42, Issue -, Pages 121-142Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-biophys-083012-130318
Keywords
entropy-enthalpy compensation; isothermal titration calorimetry; small-molecule ligand engineering
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Funding
- NCI NIH HHS [P30 CA008748] Funding Source: Medline
- NIGMS NIH HHS [R15 GM096257, 1R15GM096257-01A1] Funding Source: Medline
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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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