title: Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models.
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.
authors.affiliation: Department of Mathematics, Computer Science and Bioinformatics, Free University Berlin, Arnimallee 6, 14195 Berlin, Germany.
authors.forename: Nuria
authors.initials: N
authors.lastname: Plattner
authors.affiliation: Department of Mathematics, Computer Science and Bioinformatics, Free University Berlin, Arnimallee 6, 14195 Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Noé
mesh_terms: D001550:Benzamidines / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D007700:Kinetics; D008024:Ligands; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001550:Benzamidines; D008024:Ligands; D014361:Trypsin Inhibitors; D014357:Trypsin; C032157:benzamidine