The Thermodynamics of Protein–Ligand Interaction and Solvation: Insights for Ligand Design

• Published in: Journal of molecular biology Vol. 384; no. 4; pp. 1002 - 1017
• Main Authors: Olsson, Tjelvar S.G., Williams, Mark A., Pitt, William R., Ladbury, John E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 26.12.2008
• Subjects: isothermal titration calorimetry; Ligands; Protein Binding; protein structure; Protein Structure, Quaternary; Proteins - metabolism; protein–ligand interaction; solvent-accessible surface; Thermodynamics; CSA; protein structure; isothermal titration calorimetry; solvent-accessible surface; protein–ligand interaction; thermodynamics; ITC; SCORPIO; SMILES; ASA; PDB
• DOI: 10.1016/j.jmb.2008.09.073
• ISSN: 0022-2836

Isothermal titration calorimetry is able to provide accurate information on the thermodynamic contributions of enthalpy and entropy changes to free energies of binding. The Structure/Calorimetry of Reported Protein Interactions Online database of published isothermal titration calorimetry studies and structural information on the interactions between proteins and small-molecule ligands is used here to reveal general thermodynamic properties of protein–ligand interactions and to investigate correlations with changes in solvation. The overwhelming majority of interactions are found to be enthalpically favoured. Synthetic inhibitors and biological ligands form two distinct subpopulations in the data, with the former having greater average affinity due to more favourable entropy changes on binding. The greatest correlation is found between the binding free energy and apolar surface burial upon complex formation. However, the free-energy contribution per unit area buried is only 30–50% of that expected from earlier studies of transfer free energies of small molecules. A simple probability-based estimator for the maximal affinity of a binding site in terms of its apolar surface area is proposed. Polar surface area burial also contributes substantially to affinity but is difficult to express in terms of unit area due to the small variation in the amount of polar surface buried and a tendency for cancellation of its enthalpic and entropic contributions. Conventionally, the contribution of apolar desolvation to affinity is attributed to gain of entropy due to solvent release. Although data presented here are supportive of this notion, because the correlation of entropy change with apolar surface burial is relatively weak, it cannot, on present evidence, be confidently considered to be correct. Further, thermodynamic changes arising from small differences between ligands binding to individual proteins are relatively large and, in general, uncorrelated with changes in solvation, suggesting that trends identified across widely differing proteins are of limited use in explaining or predicting the effects of ligand modifications.