Motifs for Molecular Recognition Exploiting Hydrophobic Enclosure in Protein-Ligand Binding

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-01, Vol.104 (3), p.808-813
• Main Authors: Young, Tom, Abel, Robert, Kim, Byungchan, Berne, Bruce J., Friesner, Richard A.
• Format: Article
• Language: English
• Subjects: Active sites; Amino Acid Motifs; Antibodies - chemistry; Antibodies - metabolism; Atoms; Binding Sites; Biological Sciences; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Entropy; HIV Protease - chemistry; HIV Protease - metabolism; Hydrogen; Hydrogen bonds; Hydrophobic and Hydrophilic Interactions; Ligands; Models, Molecular; Molecular biology; Molecular dynamics; Molecules; Physical Sciences; Protein Binding; Protein Structure, Tertiary; Proteins - chemistry; Proteins - metabolism; Simulation; Solvation; Solvents; Thermodynamics; Water - chemistry; Water - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0610202104

The thermodynamic properties and phase behavior of water in confined regions can vary significantly from that observed in the bulk. This is particularly true for systems in which the confinement is on the molecular-length scale. In this study, we use molecular dynamics simulations and a powerful solvent analysis technique based on inhomogenous solvation theory to investigate the properties of water molecules that solvate the confined regions of protein active sites. Our simulations and analysis indicate that the solvation of protein active sites that are characterized by hydrophobic enclosure and correlated hydrogen bonds induce atypical entropic and enthalpic penalties of hydration. These penalties apparently stabilize the protein-ligand complex with respect to the independently solvated ligand and protein, which leads to enhanced binding affinities. Our analysis elucidates several challenging cases, including the super affinity of the streptavidin-biotin system.