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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
