Cyrus Levinthal Distinguished University Professor of Chemistry and Biophysics; Warner-Lambert/Parke-Davis Professor of Chemistry; Director of Biophysics
brookscl@umich.eduOffice Information:
2006A Chemistry
phone: 734.647.6682
Imaging & Spectroscopy; Chemical Biology; Catalysis; Theory & Computation; Physical Chemistry; Biomacromolecular Chemistry; Pharmaceutical Chemistry; Energy & Environmental Chemistry; Chemistry; Macromolecular Nanochemistry
Education/Degree:
Ph.D., Purdue University; PostDoc, Harvard UniversityAbout
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.
Representative Publications
Aggarwal, A., May, E. R., Brooks, C. L., III & Klug, W. S. Nonuniform elastic properties of macromolecules and effect of prestrain on their continuum nature. Phys Rev E Stat Nonlin Soft Matter Phys, 93, 012417 (2016).
Arthur, E. J. & Brooks, C. L., III. Parallelization and improvements of the generalized born model with a simple sWitching function for modern graphics processors. J Comput Chem, 37, 927-939 (2016).
Arthur, E. J. & Brooks, C. L., III. Efficient implementation of constant pH molecular dynamics on modern graphics processors. J Comput Chem, 37, 2171-2180 (2016).
Bruno, P. A., Morriss-Andrews, A., Henderson, A. R., Brooks, C. L., III & Mapp, A. K. A Synthetic Loop Replacement Peptide That Blocks Canonical NF-kappaB Signaling. Angew Chem Int Ed Engl, 55, 14997-15001 (2016).
Dickson, A., Ahlstrom, L. S. & Brooks, C. L., III. Coupled folding and binding with 2D Window-Exchange Umbrella Sampling. J Comput Chem, 37, 587-594 (2016).
Gagnon, J. K., Law, S. M. & Brooks, C. L., III. Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM. J Comput Chem, 37, 753-762 (2016).
Horowitz, S., Salmon, L., Koldewey, P., Ahlstrom, L. S., Martin, R., Quan, S., Afonine, P. V., van den Bedem, H., Wang, L., Xu, Q., Trievel, R. C., Brooks, C. L., III & Bardwell, J. C. Visualizing chaperone-assisted protein folding. Nature structural & molecular biology, 23, 691-697 (2016).
Lee, J., Cheng, X., Swails, J. M., Yeom, M. S., Eastman, P. K., Lemkul, J. A., Wei, S., Buckner, J., Jeong, J. C., Qi, Y., Jo, S., Pande, V. S., Case, D. A., Brooks, C. L., III, MacKerell, A. D., Jr., Klauda, J. B. & Im, W. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput, 12, 405-413 (2016).
Mustoe, A. M., Al-Hashimi, H. M. & Brooks, C. L., III. Secondary structure encodes a cooperative tertiary folding funnel in the Azoarcus ribozyme. Nucleic Acids Res., 44, 402-412 (2016).
Post, C. B. & Brooks, C. L., III. Editorial. Protein Sci., 25, 5-8 (2016).
Salmon, L., Ahlstrom, L. S., Horowitz, S., Dickson, A., Brooks, C. L., III & Bardwell, J. C. Capturing a Dynamic Chaperone-Substrate Interaction Using NMR-Informed Molecular Modeling. J. Am. Chem. Soc., 138, 9826-9839 (2016).
Soteras Gutierrez, I., Lin, F. Y., Vanommeslaeghe, K., Lemkul, J. A., Armacost, K. A., Brooks, C. L., III & MacKerell, A. D., Jr. Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions. Bioorg Med Chem, 24, 4812-4825 (2016).
Won, S. J., Davda, D., Labby, K. J., Hwang, S. Y., Pricer, R., Majmudar, J. D., Armacost, K. A., Rodriguez, L. A., Rodriguez, C. L., Chong, F. S., Torossian, K. A., Palakurthi, J., Hur, E. S., Meagher, J. L., Brooks, C. L., III, Stuckey, J. A. & Martin, B. R. Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2). ACS Chem Biol, 11, 3374-3382 (2016).
Daher, M., Mustoe, A. M., Morriss-Andrews, A., Brooks, C. L., III & Walter, N. G. Tuning RNA folding and function through rational design of junction topology. Nucleic Acids Res., 45, 9706-9715 (2017).
Ding, X., Vilseck, J. Z., Hayes, R. L. & Brooks, C. L., III. Gibbs Sampler-Based lambda-Dynamics and Rao-Blackwell Estimator for Alchemical Free Energy Calculation. J Chem Theory Comput, 13, 2501-2510 (2017).
Hayes, R. L., Armacost, K. A., Vilseck, J. Z. & Brooks, C. L., III. Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite lambda Dynamics. J Phys Chem B, 121, 3626-3635 (2017).
Kamgar-Parsi, K., Hong, L., Naito, A., Brooks, C. L., III & Ramamoorthy, A. Growth-incompetent monomers of human calcitonin lead to a noncanonical direct relationship between peptide concentration and aggregation lag time. J Biol Chem, 292, 14963-14976 (2017).
Kim, S., Lee, J., Jo, S., Brooks, C. L., III, Lee, H. S. & Im, W. CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules. J Comput Chem, 38, 1879-1886 (2017).
Su, M., Guo, E. Z., Ding, X., Li, Y., Tarrasch, J. T., Brooks, C. L., III, Xu, Z. & Skiniotis, G. Mechanism of Vps4 hexamer function revealed by cryo-EM. Science Advances, 3, e1700325 (2017).
Wei, S., Ahlstrom, L. S. & Brooks, C. L., III. Exploring Protein-Nanoparticle Interactions with Coarse-Grained Protein Folding Models. Small, 13 (2017).
Wei, S., Brooks, C. L., III & Frank, A. T. A rapid solvent accessible surface area estimator for coarse grained molecular simulations. J Comput Chem, 38, 1270-1274 (2017).
Zou, X., Wei, S., Jasensky, J., Xiao, M., Wang, Q., Brooks, C. L., III & Chen, Z. Molecular Interactions between Graphene and Biological Molecules. J. Am. Chem. Soc., 139, 1928-1936 (2017).
Deng, H., Ke, S., Callender, R., Balakrishnan , G., Spiro, T., May, E. R. & Brooks, C. L., III. Structural Interpretations of the Observed Catalytic Loop Dynamics of Yersinia Protein Tyrosine Phosphatase by NEB/HFB Computational Biochemistry, submitted for publication (2018).
Ding, X., Hayes, R. L., Vilseck, J. Z., Charles, M. K. & Brooks, C. L., III. CDOCKER and lambda-dynamics for prospective prediction in D(3)R Grand Challenge 2. J Comput Aided Mol Des, 32, 89-102 (2018).
Ho, P. T., Monteil-Garcia, D., Wong, J. J., Carrillo-Tripp, M., Brooks, C. L., III, Johnson, J. E. & Reddy, V. S. VIPERdb: A Tool for Virus Research. Ann Rev Virol, in the press (2018).
Li, Y., Ogorzalek, T. L., Wei, S., Zhang, X., Yang, P., Jasensky, J., Brooks, C. L., III, Marsh, E. N. G. & Chen, Z. Effect of immobilization site on the orientation and activity of surface-tethered enzymes. Phys Chem Chem Phys, 20, 1021-1029 (2018).
Vilseck, J., Armacost, K. A., Hayes, R. L., Goh, G. B. & Brooks, C. L., III. Predicting Binding Free Energies in a Combinatorial Chemical Space Using Multisite Lambda Dynamics. submitted for publication (2018).
Widom, J., Hayes, R. L., Nedialkov, Y., Rai, V., Brooks, C. L., III & Walter, N. G. Ligand Modulates Cross-Coupling between Riboswitch Folding and Transcriptional Pausing. submitted for publication (2018).
Xiao, M., Wei, S., Li, Y., Jasensky, J., Chen, J., Brooks, C. L., III & Chen, Z. Molecular Interactions between Single Layered MoS2 and Biological Molecules. Chem Sci, in the press (2018).
Award(s)
- President of the Protein Society, 2017-2020
- Fellow of the Biophysical Society, 2017
- Hans Neurath Award-Protein Society, 2012
- Alfred P. Sloan Foundation Fellow
- Fellow of the Biophysical Society
- Fellow of the Royal Society of Chemistry
- Fellow of the American Association for the Advancement of Science
- North American Editor-in-Chief of the Journal of Computational Chemistry
- Computer World/Smithsonian Award in Computational Science
About
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.
Representative Publications
Aggarwal, A., May, E. R., Brooks, C. L., III & Klug, W. S. Nonuniform elastic properties of macromolecules and effect of prestrain on their continuum nature. Phys Rev E Stat Nonlin Soft Matter Phys, 93, 012417 (2016).
Arthur, E. J. & Brooks, C. L., III. Parallelization and improvements of the generalized born model with a simple sWitching function for modern graphics processors. J Comput Chem, 37, 927-939 (2016).
Arthur, E. J. & Brooks, C. L., III. Efficient implementation of constant pH molecular dynamics on modern graphics processors. J Comput Chem, 37, 2171-2180 (2016).
Bruno, P. A., Morriss-Andrews, A., Henderson, A. R., Brooks, C. L., III & Mapp, A. K. A Synthetic Loop Replacement Peptide That Blocks Canonical NF-kappaB Signaling. Angew Chem Int Ed Engl, 55, 14997-15001 (2016).
Dickson, A., Ahlstrom, L. S. & Brooks, C. L., III. Coupled folding and binding with 2D Window-Exchange Umbrella Sampling. J Comput Chem, 37, 587-594 (2016).
Gagnon, J. K., Law, S. M. & Brooks, C. L., III. Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM. J Comput Chem, 37, 753-762 (2016).
Horowitz, S., Salmon, L., Koldewey, P., Ahlstrom, L. S., Martin, R., Quan, S., Afonine, P. V., van den Bedem, H., Wang, L., Xu, Q., Trievel, R. C., Brooks, C. L., III & Bardwell, J. C. Visualizing chaperone-assisted protein folding. Nature structural & molecular biology, 23, 691-697 (2016).
Lee, J., Cheng, X., Swails, J. M., Yeom, M. S., Eastman, P. K., Lemkul, J. A., Wei, S., Buckner, J., Jeong, J. C., Qi, Y., Jo, S., Pande, V. S., Case, D. A., Brooks, C. L., III, MacKerell, A. D., Jr., Klauda, J. B. & Im, W. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput, 12, 405-413 (2016).
Mustoe, A. M., Al-Hashimi, H. M. & Brooks, C. L., III. Secondary structure encodes a cooperative tertiary folding funnel in the Azoarcus ribozyme. Nucleic Acids Res., 44, 402-412 (2016).
Post, C. B. & Brooks, C. L., III. Editorial. Protein Sci., 25, 5-8 (2016).
Salmon, L., Ahlstrom, L. S., Horowitz, S., Dickson, A., Brooks, C. L., III & Bardwell, J. C. Capturing a Dynamic Chaperone-Substrate Interaction Using NMR-Informed Molecular Modeling. J. Am. Chem. Soc., 138, 9826-9839 (2016).
Soteras Gutierrez, I., Lin, F. Y., Vanommeslaeghe, K., Lemkul, J. A., Armacost, K. A., Brooks, C. L., III & MacKerell, A. D., Jr. Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions. Bioorg Med Chem, 24, 4812-4825 (2016).
Won, S. J., Davda, D., Labby, K. J., Hwang, S. Y., Pricer, R., Majmudar, J. D., Armacost, K. A., Rodriguez, L. A., Rodriguez, C. L., Chong, F. S., Torossian, K. A., Palakurthi, J., Hur, E. S., Meagher, J. L., Brooks, C. L., III, Stuckey, J. A. & Martin, B. R. Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2). ACS Chem Biol, 11, 3374-3382 (2016).
Daher, M., Mustoe, A. M., Morriss-Andrews, A., Brooks, C. L., III & Walter, N. G. Tuning RNA folding and function through rational design of junction topology. Nucleic Acids Res., 45, 9706-9715 (2017).
Ding, X., Vilseck, J. Z., Hayes, R. L. & Brooks, C. L., III. Gibbs Sampler-Based lambda-Dynamics and Rao-Blackwell Estimator for Alchemical Free Energy Calculation. J Chem Theory Comput, 13, 2501-2510 (2017).
Hayes, R. L., Armacost, K. A., Vilseck, J. Z. & Brooks, C. L., III. Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite lambda Dynamics. J Phys Chem B, 121, 3626-3635 (2017).
Kamgar-Parsi, K., Hong, L., Naito, A., Brooks, C. L., III & Ramamoorthy, A. Growth-incompetent monomers of human calcitonin lead to a noncanonical direct relationship between peptide concentration and aggregation lag time. J Biol Chem, 292, 14963-14976 (2017).
Kim, S., Lee, J., Jo, S., Brooks, C. L., III, Lee, H. S. & Im, W. CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules. J Comput Chem, 38, 1879-1886 (2017).
Su, M., Guo, E. Z., Ding, X., Li, Y., Tarrasch, J. T., Brooks, C. L., III, Xu, Z. & Skiniotis, G. Mechanism of Vps4 hexamer function revealed by cryo-EM. Science Advances, 3, e1700325 (2017).
Wei, S., Ahlstrom, L. S. & Brooks, C. L., III. Exploring Protein-Nanoparticle Interactions with Coarse-Grained Protein Folding Models. Small, 13 (2017).
Wei, S., Brooks, C. L., III & Frank, A. T. A rapid solvent accessible surface area estimator for coarse grained molecular simulations. J Comput Chem, 38, 1270-1274 (2017).
Zou, X., Wei, S., Jasensky, J., Xiao, M., Wang, Q., Brooks, C. L., III & Chen, Z. Molecular Interactions between Graphene and Biological Molecules. J. Am. Chem. Soc., 139, 1928-1936 (2017).
Deng, H., Ke, S., Callender, R., Balakrishnan , G., Spiro, T., May, E. R. & Brooks, C. L., III. Structural Interpretations of the Observed Catalytic Loop Dynamics of Yersinia Protein Tyrosine Phosphatase by NEB/HFB Computational Biochemistry, submitted for publication (2018).
Ding, X., Hayes, R. L., Vilseck, J. Z., Charles, M. K. & Brooks, C. L., III. CDOCKER and lambda-dynamics for prospective prediction in D(3)R Grand Challenge 2. J Comput Aided Mol Des, 32, 89-102 (2018).
Ho, P. T., Monteil-Garcia, D., Wong, J. J., Carrillo-Tripp, M., Brooks, C. L., III, Johnson, J. E. & Reddy, V. S. VIPERdb: A Tool for Virus Research. Ann Rev Virol, in the press (2018).
Li, Y., Ogorzalek, T. L., Wei, S., Zhang, X., Yang, P., Jasensky, J., Brooks, C. L., III, Marsh, E. N. G. & Chen, Z. Effect of immobilization site on the orientation and activity of surface-tethered enzymes. Phys Chem Chem Phys, 20, 1021-1029 (2018).
Vilseck, J., Armacost, K. A., Hayes, R. L., Goh, G. B. & Brooks, C. L., III. Predicting Binding Free Energies in a Combinatorial Chemical Space Using Multisite Lambda Dynamics. submitted for publication (2018).
Widom, J., Hayes, R. L., Nedialkov, Y., Rai, V., Brooks, C. L., III & Walter, N. G. Ligand Modulates Cross-Coupling between Riboswitch Folding and Transcriptional Pausing. submitted for publication (2018).
Xiao, M., Wei, S., Li, Y., Jasensky, J., Chen, J., Brooks, C. L., III & Chen, Z. Molecular Interactions between Single Layered MoS2 and Biological Molecules. Chem Sci, in the press (2018).
Award(s)
- President of the Protein Society, 2017-2020
- Fellow of the Biophysical Society, 2017
- Hans Neurath Award-Protein Society, 2012
- Alfred P. Sloan Foundation Fellow
- Fellow of the Biophysical Society
- Fellow of the Royal Society of Chemistry
- Fellow of the American Association for the Advancement of Science
- North American Editor-in-Chief of the Journal of Computational Chemistry
- Computer World/Smithsonian Award in Computational Science
