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  • Title: Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models.
    Author: Plattner N, Noé F.
    Journal: Nat Commun; 2015 Jul 02; 6():7653. PubMed ID: 26134632.
    Abstract:
    Understanding the structural mechanisms of protein-ligand binding and their dependence on protein sequence and conformation is of fundamental importance for biomedical research. Here we investigate the interplay of conformational change and ligand-binding kinetics for the serine protease Trypsin and its competitive inhibitor Benzamidine with an extensive set of 150 μs molecular dynamics simulation data, analysed using a Markov state model. Seven metastable conformations with different binding pocket structures are found that interconvert at timescales of tens of microseconds. These conformations differ in their substrate-binding affinities and binding/dissociation rates. For each metastable state, corresponding solved structures of Trypsin mutants or similar serine proteases are contained in the protein data bank. Thus, our wild-type simulations explore a space of conformations that can be individually stabilized by adding ligands or making suitable changes in protein sequence. These findings provide direct evidence of conformational plasticity in receptors.
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