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 I

42-POS Board 42 Multiple Pre-Existence of Conformations Underpinning Allosteric Activation of Gal3p in Galactose Signal Transduction Kharerin Hungyo , Rajesh K. Kar, Ranjith Padinhateeri, Paike J. Bhat. Indian institute of Technology Bombay, Mumbai, India. Conformational dynamics of protein has been considered as one of the key driving forces regulating cellular signaling. Signaling proteins have been shown to pre-exist predominantly in inactive conformation (I) untill a ligand or mutation induces a population shift in favor of the formerly less populated active conformation (A). However, the transition(s) between inactive and active conformational states has not been clearly elucidated. Here we investigate the dynamic stability and the role of amino acids involved in stabilization and intra-domain signal communications in Gal3p, a signal transducer protein in GAL genetic switch of Saccharomyces cerevisiae . Gal3p is known to exist in multiple conformational states (I and A). In response to galactose, Gal3p switches from open conformation (I) to closed conformation (A), to activate transcription of GAL genes. Closed and open conformer dynamics using canonical molecular dynamics (CMD) simulations were carried out for the wild type protein and its mutant variants. Distribution of the domain-lip distance from closed and open conformer dynamics shows a bimodal behavior for the former, while demonstrating a gaussian unimodal for the latter. Using hydrogen bond (H-bond) network analysis from CMD, we identified set(s) of conserved H- bonded amino acid pairs that are spaced far apart in the primary structure of the protein(s). Our results suggest the presence of a typical signature of H-bonded network specific to the state of the protein (open or closed) as well as varying H-bonded network for different mutant variants which could play a crucial role in determining their dynamic stability. We also used targeted molecular dynamics (TMD) simulations to study the free energy landscape along the transitional pathways from state 'I' to state 'A' in order to identify the transitional structures (local minima) encountered during the structural switching.

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