Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

74-POS Board 27 Binding-Competent States for L-arginine in E. coli Arginine Repressor Apoprotein Saurabh K. Pandey 1,2 , David Reha 1,2 , Vasilina Zayats 1,2 , Milan Melichercik 1,3 , Jannette Carey 4 , Rudiger Ettrich 1,2 . 1 Academy of Sciences of the Czech Republic, Nove Hrady, Czech Republic, 2 University of South Bohemia, Nove Hrady, Czech Republic, 4 Princeton University, Princeton, NJ, USA. 3 Comenius University, Bratislava, Slovakia. Arginine repressor of E. coli is a multifunctional hexameric protein that provides feedback regulation of arginine metabolism upon activation by the negatively cooperative binding of L- arginine. A molecular mechanism of allostery has been described earlier in which conserved arginine and aspartate residues in each ligand-binding pocket promote rotational oscillation of the trimers within the hexameric domain that binds L-arginine by engagement and release of hydrogen-bonded salt bridges. Binding of exogenous L-arginine displaces resident arginine residues and arrests oscillation, shifting the equilibrium quaternary ensemble and promoting motions that maintain the configurational entropy of the system [1]. Interpretation of this complex system requires an understanding of the protein's conformational landscape. In this work the ~50 kDa hexameric C-terminal domain was studied by 100 ns molecular dynamics simulations in presence and absence of the six L-arg ligands that bind at the trimer-trimer interface. A rotational shift between trimers followed by rotational oscillation occurs in the production phase of the simulations only when L-arg is absent. Analysis of the system reveals that the degree of rotation is correlated with the number of hydrogen bonds across the trimer interface. The trajectory presents frames with one or more apparently open binding sites into which one L-arg could be docked successfully in three different instances, indicating that a binding-competent state of the system is occasionally sampled. Simulations of the resulting singly-liganded systems reveal for the first time that the binding of one L-arg results in a holoprotein-like conformational distribution. [1] R Strawn, M Melichercik, M Green, T Stockner, J Carey, R Ettrich (2010) Symmetric allosteric mechanism of hexameric Escherichia coli arginine repressor exploits competition between L-arginine ligands and resident arginine residues. PLOS Computational Biology 6: 6. e1000801

127