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 Session IV Abstracts

How Much Can Local Dynamical Features of Proteins Can Inform on Conformational Possibilities? Canan Atilgan . Sabanci University, Istanbul, Turkey. It is not merely the protein structure, but also accompanying dynamics that are key in deciphering potential local sites to manipulate function. Based-on the assumption that target sites other than the direct binding region exist on the protein surface and that these are allosteric modifiers of binding-region dynamics, we have developed a methodology (termed perturbation- response scanning, PRS) whereby perturbations in the form of forces are introduced at selected sites and propensity of the protein to ease into other conformations under the influence of this force is quantified(1,2). Residue-by-residue scanning proteins by such perturbations and recording the subset of residues whose perturbation potentially leads to another known conformation, we map potential target sites on the surface of the protein. We show, through molecular dynamics simulations on sample proteins, that acting on these candidate sites either directly by mutations(3) or indirectly by lowering the pH(5), conformational change may be achieved on time scales shorter than measured experimentally under uniform environmental conditions. Even in the absence of conformational change, selected point mutations manipulate functional dynamics by altering the electrostatic distribution which in turn induces subtle differences in residue fluctuations around their identical average positions. Thus, residue fluctuations in the protein are greatly altered due to effective propagation of perturbation and presence of remotely controlling residues. It is plausible that certain residues have evolved to occupy positions in electrostatically susceptible and mechanically effective positions. PRS is an efficient method that can pinpoint such positions. 1. Atilgan C, Atilgan AR. 2009. PLoS Comput. Biol. 5: e1000544 2. Atilgan C, Gerek ZN, Ozkan SB, Atilgan AR. 2010. Biophysical Journal 99: 933-43 3. Aykut AO, Atilgan AR, Atilgan C. 2013. PLoS Comput. Biol. 9: e1003366

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