Allosteric Regulation of Proteins involved in Phosporylation-based signaling

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Protein Phosphorylation is a key post-translational modification that allows for physiologically relevant signaling cascades in the cell. These phosphorylation events alter surface charges of protein thus allowing for modulation of protein-protein interactions relevant to the needs of the cell. Molecular enzymes that direct protein phosphorylation are essentially protein kinases (that phosphorylate proteins using ATP) and protein phosphatases (that remove these phosphates from proteins). A delicate balance between the opposing activities of these enzymes maintains critical signaling events in the cell. Evidently, both protein kinases and protein phosphatases are critical pharmaceutical targets for drug discovery. High conservation of the catalytic domains of these proteins and their conserved active site mechanisms continue to challenge the field that works towards targeting specific kinases or phosphatases implicated in specialized disease states. In the past decade, allosteric modulation and harmonic models of protein dynamics has gathered momentum. The present proposal combines these two aspects of protein regulation and attempts to look at dynamics-based allostery in protein kinases, phosphatases and their pseudo-enzyme forms. The proposal develops of the principals of 'String Theory' and seeks to conceptualize the energy-frequency mode of these enzymes using the Violin model of allostery. Essentially, all harmonic frequencies of the internal dynamics of these proteins are used to define their catalytic states in the form of a graph theory based community map. These maps are then used to study specific mutation states or protein complexes to decipher the roles of these allosteric modulators on the function of these enzymes.