title: Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding.
abstract: 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.
authors.affiliation: Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Young
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
authors.forename: Byungchan
authors.initials: B
authors.lastname: Kim
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Berne
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
mesh_terms: D020816:Amino Acid Motifs; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000906:Antibodies; D008024:Ligands; D011506:Proteins; D014867:Water; D051546:Cyclooxygenase 2; D016333:HIV Protease