Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models

• Published in: Nature communications Vol. 6; no. 1; p. 7653
• Main Authors: Plattner, Nuria, Noé, Frank
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 119/118; 631/154/309/2420; 631/337; 631/45/535/1267; 631/57/2272/2273; Benzamidines - chemistry; Benzamidines - metabolism; Binding Sites; Humanities and Social Sciences; Kinetics; Ligands; Markov Chains; Molecular Dynamics Simulation; multidisciplinary; Protein Binding; Protein Conformation; Proteins; Science; Science (multidisciplinary); Simulation; Trypsin - chemistry; Trypsin - metabolism; Trypsin Inhibitors - chemistry; Trypsin Inhibitors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8653

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. Conformational plasticity influences several aspects of protein function. Here the authors combine extensive MD simulations with Markov state models—using trypsin as model—to reveal new mechanistic details of how conformational plasticity influence ligand-receptors interactions.