Modeling and Theory of Biomolecular Association

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This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The association of ligand and protein is of fundamental importance in biology, playing roles in functions as diverse as immunity, metabolism, signaling, and cognition. Recent advances on Brownian dynamics and continuum simulation methods provide powerful tools to study diffusion in biomolecular systems, but they are mostly restricted to systems that are near the limit of diffusion-control one-step association processes. For more complicated processes, such as two-step association processes that involve short-range interactions and conformational changes of ligands and proteins, existing methods may not be reliable enough to study the association pathways and predict the rate constants. This project will develop new computer simulation tools and theoretical models to study the two-step binding processes. This work will be carried out in three integrated steps: First, new multi-scale methods, combining Brownian dynamics simulation methods and continuum simulation methods to study ligand-protein encounters and association rate constants will be developed. Second, the new codes will be modified for field programmable gate arrays (FPGAs). Notably, FPGAs are new hardware code accelerators that can largely speedup the calculations. Third, free energy profile of binding pathways, energy barriers and kinetic and thermodynamic properties of ligand-receptor association and dissociation will be computed by several widely used molecular simulation packages and methods to be developed. The PI will integrate the research activities with education at different levels. The training of young scientists, including graduate students, undergraduates, as well as postdoctoral fellows, will be a central focus of the PI's group. The PI strongly encourages undergraduates from underrepresented groups in science to participate in the research. Local high school students will also have the opportunity to gain research experience in the PI's lab through a variety of programs at the PI's institution. The PI will distribute all codes developed in this project.