Dynamics Govern Specificity of a Protein-Protein Interface: Substrate Recognition by Thrombin.
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.
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria; Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Julian E
JE
Fuchs
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Roland G
RG
Huber
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Birgit J
BJ
Waldner
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Ursula
U
Kahler
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Susanne
S
von Grafenstein
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Christian
C
Kramer
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Klaus R
KR
Liedl
D001665:Binding Sites; D003198:Computer Simulation; D019277:Entropy; D005340:Fibrinogen / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D013379:Substrate Specificity; D013816:Thermodynamics; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism*; D014867:Water
D010455:Peptides; D014867:Water; D005340:Fibrinogen; D013917:Thrombin