CAREER: Computational Investigation of Structural and Dynamical Mechanisms of Protein Regulation by Post-Translational Phosphorylation

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The objective of this project is to develop a physics-based theory for predicting protein conformational change caused by phosphorylation. Protein post-translational phosphorylation is a ubiquitous mechanism for cellular regulation that plays a central role in such diverse processes as signal transduction, transport, and metabolism. The central hypothesis is that the diverse responses to phosphorylation can be better understood and systematized by viewing the introduction of the phosphate charge as a perturbation to the protein energy landscape. The computational methods employed range from quantum mechanics to molecular mechanics with implicit salvation models. From a practical perspective, this research will result in a computer program that is capable of predicting atomic-level response to phosphorylation for many proteins with known phosphorylation sites but no experimentally determined structure in the phosphorylated form. This CAREER award will support research and teaching activities that lie at the intersection of physics, computational science, and biology. The PI is developing a new interdisciplinary graduate-level course and practicum centered on the application of physical and computational chemistry to biology. The practicum will permit hands-on experience with many modeling methods, including software developed under this grant and prior NSF support. All examples from the practicum, generated by the instructor and students, will be made available on-line, creating a broadly available resource. The research component also involves the direct participation of scientists from the underrepresented groups, as well as a collaboration involving undergraduate students at the Stern College for Women, Yeshiva University. Finally, all algorithms developed by the PI will be encapsulated in an easy-to-use software package, which is available free-of-charge for all academic purposes.