Understanding the forces that determine the structure, dynamics and reactivity of proteins, peptides, nucleic acids, and complexes containing these molecules, and the processes by which the structures are adopted is essential to extend our knowledge of the molecular nature of structure and function. To address such questions, we develop new methods from statistical mechanics, quantum mechanics and statistical modeling and utilize these methods in molecular simulations to study structure/function/reactivity relationships in systems of biological importance.
Ongoing efforts in the Brooks Group are directed toward answering critical questions that provide insights into function and inform experiment on key problems in biomedicine, e.g., drug discovery and refinement, protein-protein interactions, protein/enzyme engineering and re-engineering, protein folding and misfolding, and in biological function that results from or in large scale assembly or reorganization of biological macromolecules and their assemblies. Our group focuses on fundamental methodological developments but also engages extensively in collaborative efforts with our experimental colleagues at the University of Michigan and elsewhere.
Current projects include drug discovery and design through the development and application of cutting edge free energy simulation methods and small molecule docking approaches; fundamental investigations of the role that pH plays in modulating and mediating molecular processes in the context of cellular physiology. Protein folding and misfolding, protein-protein association and the interactions of intrinsically disordered proteins with their protein targets are also being pursued through collaborative studies, including one focused on transcriptional activation. The re-design of enzymes to exploit their exquisite control of stereo- and/or region-specific chemistry for pharmaceutically interesting chemical syntheses. The development and application of machine learning methods, and protein ancestral reconstruction approaches are also being utilized in the context of many of the above noted problems.
Significant computational resources are necessary to realize these objectives, and this need motivates our efforts aimed at the efficient use of new computer architectures, including large supercomputers and computational grids. We are a key site for the development of the CHARMM software and work extensively on its continued development and the implementation of critical computational kernels on advanced computational hardware, including graphically processing units (GPUs). Our group oversees a local computing facility of approximately 5000 cpu cores and 300 GPUs, which facilitate the development and many of the applications noted above.