Regulation of Protein Phosphorylation: Energy Landscapes, Allostery and Dynamic Regulation
December 05, 2008 – December 07, 2008
San Diego, California
Susan S. Taylor
J. Andrew McCammon
David E. Shaw
The field of protein phosphorylation is at an exciting transition point and offers a unique and unprecedented opportunity to bridge theoretical and experimental interfaces at many levels. It is a major mechanism for regulation in eukaryotic cells and is thus at the center of signal transduction. It is a highly dynamic process at the level of the kinases and phosphatases as well as the target proteins and is also a process that depends critically on spatial and temporal dynamics within the cell. Major advances in the two years since we held our last ICAM conference make the next conference especially timely for pioneering new opportunities at this interface. As more and more protein kinase structures are solved, in particular as part of complexes with their substrates and with scaffold proteins, we are beginning to more comprehensively understand and appreciate the mechanistic, allosteric, and dynamic properties of these regulatory “molecular switches” in ways that were simply not possible before. The recent NMR analysis of protein kinases and their modulatory domains also allow us for the first time to have residue-specific information on global dynamics and allostery. At the same time, solution methods such as small angle X-ray scattering give us a global picture of molecular motions. In parallel with the large amounts of structural data, there have been significant advances in molecular dynamics calculations that allow for the real-time correlation of dynamics observed by other biophysical techniques. Bridging these time scales has not been possible previously. A final new factor is the advance in computational hardware for carrying out simulations. The integration of all of these advances is what we hope to capture in this meeting. Protein phosphorylation, in general, and protein kinases, in particular, provide a wonderful system for bringing together molecular dynamics, molecular recognition, and order/disorder transitions. One can delve deeply into the evolution of this enzyme family and decipher explanations for the co-evolution of distant residues and the evolution of allostery. Eventually, we can also hopefully correlate these findings with disease genotypes.
The ICAM Symposium that was held in San Diego in 2005 was very exciting, and most of the participants are quite enthusiastic about having a follow up meeting given the progress discussed above. We hope to frame this meeting in a “think tank” mode where we not only discuss the most recent advances and attempt to traverse interdisciplinary boundaries between the theorists and the experimentalists, but also try to establish goals and opportunities for moving forward by building multidisciplinary and collaborative frameworks. We will organize the talks around specific themes, but then also use breakout sessions (such as lunch and breakfast) for discussing how we might most effectively advance our understanding. What are the most important questions? What are the greatest challenges? What are the opportunities for collaborative funding? How can we better understand the dynamic behavior of individual molecules and how can we model the dynamic behavior of cells that they regulate? These will be questions that will permeate the entire meeting and will drive future collaborations to implement our conclusions. We will schedule two days of talks and then devote the last morning entirely to a discussion of future directions and specific follow-up plans. We believe that protein phosphorylation is at a critical transition time, and that a follow-up ICAM Symposium along the lines discussed above could be truly transforming for the field.