Abstract
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.
Highlights
Cellular signaling critically depends on biomolecular recognition processes [1]
Conformational selection has become apparent in most biomolecular recognition processes [7]
Mapping to the binding site region gives a visual impression of intrinsic dynamics of the thrombin substrate binding cleft
Summary
Cellular signaling critically depends on biomolecular recognition processes [1]. Understanding these processes on the molecular level is key for a comprehensive picture of living organisms. We quantified thrombin sub-pocket specificity as cleavage entropy [16] based on substrate data from MEROPS [13] (see Fig 1). To probe intrinsic local dynamics of the binding site region of thrombin without ligand, we calculated residue-wise backbone flexibility in holo state using Cα B-factors after a global alignment.
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