title: Detecting Allosteric Networks Using Molecular Dynamics Simulation.
abstract: Allosteric networks allow enzymes to transmit information and regulate their catalytic activities over vast distances. In principle, molecular dynamics (MD) simulations can be used to reveal the mechanisms that underlie this phenomenon; in practice, it can be difficult to discern allosteric signals from MD trajectories. Here, we describe how MD simulations can be analyzed to reveal correlated motions and allosteric networks, and provide an example of their use on the coagulation enzyme thrombin. Methods are discussed for calculating residue-pair correlations from atomic fluctuations and mutual information, which can be combined with contact information to identify allosteric networks and to dynamically cluster a system into highly correlated communities. In the case of thrombin, these methods show that binding of the antagonist hirugen significantly alters the enzyme's correlation landscape through a series of pathways between Exosite I and the catalytic core. Results suggest that hirugen binding curtails dynamic diversity and enforces stricter venues of influence, thus reducing the accessibility of thrombin to other molecules.
authors: Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, IL, United States.
authors: S
authors: S
authors: Bowerman
authors: Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, IL, United States. Electronic address: jwereszc@iit.edu.
authors: J
authors: J
authors: Wereszczynski
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D020134:Catalytic Domain; D002712:Chlorides / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006629:Hirudins / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D012964:Sodium / Q000737:chemistry; D013917:Thrombin / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D002712:Chlorides; D006629:Hirudins; D010446:Peptide Fragments; D014867:Water; C062510:hirugen; D006493:Heparin; D012964:Sodium; D013917:Thrombin
keywords: Allosteric networks; Community analysis; Correlated motion; Molecular dynamics