Dynamics Govern Specificity of a Protein-Protein Interface: Substrate Recognition by Thrombin

• Published in: PloS one Vol. 10; no. 10; p. e0140713
• Main Authors: Fuchs, Julian E, Huber, Roland G, Waldner, Birgit J, Kahler, Ursula, von Grafenstein, Susanne, Kramer, Christian, Liedl, Klaus R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.10.2015; Public Library of Science (PLoS)
• Subjects: Amino acids; Binding Sites; Computer Simulation; Crystal structure; Drug development; Entropy; Enzymes; Fibrinogen - metabolism; Hydration; Hydrogen Bonding; Interfaces; Models, Molecular; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Pattern recognition; Peptides - metabolism; Protein Binding; Proteins; Signal transduction; Substrate Specificity; Substrates; Theory; Thermodynamics; Thrombin; Thrombin - chemistry; Thrombin - metabolism; Water; Austria
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140713

Biomolecular recognition is crucial in cellular signal transduction. Signaling is mediated through molecular interactions at protein-protein interfaces. Still, specificity and promiscuity of protein-protein interfaces cannot be explained using simplistic static binding models. Our study rationalizes specificity of the prototypic protein-protein interface between thrombin and its peptide substrates relying solely on binding site dynamics derived from molecular dynamics simulations. We find conformational selection and thus dynamic contributions to be a key player in biomolecular recognition. Arising entropic contributions complement chemical intuition primarily reflecting enthalpic interaction patterns. The paradigm "dynamics govern specificity" might provide direct guidance for the identification of specific anchor points in biomolecular recognition processes and structure-based drug design.