Charles L. Brooks III

Warner-Lambert/Parke-Davis Professor of Chemistry and Professor of Biophysics

Ph.D., Purdue University
PostDoc, Harvard University

Research Focus: Physical Chemistry / Biophysical Chemistry / Theoretical and Computational Chemistry and Biophysics

Phone: 734.647.6682
E-mail: brookscl@umich.edu
Fax: : 734.647.1604

Understanding the forces that determine the structure of proteins, peptides, nucleic acids, their complexes and assemblies, as well as the processes by which the structures are adopted is essential to extend our knowledge of the molecular nature of structure and function. Furthermore, exploring how to modulate and control these processes using small molecule “chemical probes” is critical to advancing our understanding of biological function in the laboratory and in cellular contexts. To address such questions, we use the theoretical frameworks of statistical mechanics, molecular simulations, statistical modeling, and quantum chemistry, and collaborate extensively with out colleagues to develop quantitative models for these critical elements of biological function. 

Creating atomic-level models to simulate biophysical processes (e.g., folding of a protein or binding of a ligand to a biological receptor) requires (1) the development of potential energy functions that accurately represent the atomic interactions and (2) the use of quantum chemistry to aid in parameterizing these models. Calculation of thermodynamic properties requires the development and implementation of new theoretical and computational approaches that connect averages over atomistic descriptions to experimentally measurable thermodynamic and kinetic properties. Thus, as part of the tool set essential for our work we develop novel methods of protein-ligand docking approaches, free energy methods that enable the rapid in silicon screening of many 100s of compounds within the rigorous framework of statistical mechanics and mechanical models that provide quantitative predictions of protein and nucleic acid structure-function relationships.


Interpreting experimental results at more microscopic levels is fueled by the development and investigation of theoretical models for the processes of interest, which range from atomic level detail to more coarse-grained molecular representations of the system. Massive computational resources are needed to realize these objectives, and this need motivates our efforts aimed at the efficient use of new computer architectures, including large supercomputers, Linux Beowulf clusters, computational grids and GPU-accelerated modeling approaches. Each of the objectives and techniques mentioned represents an ongoing area of development within our research program.


Brooks Research Group



2012 Hans Neurath Award-Protein Society
2000-2010 Named one of “Top 100 Chemists of the Decade by Thomson Reuters
  John H. Abel Award, American Society for Pharmacology and Experimental Therapeutics
  Alfred P. Sloan Foundation Fellow
  Fellow of the American Association for the Advancement of Science
  North American Editor of the Journal of Computational Chemistry
  Computer World/Smithsonian Award in Computational Science


Representative Publications

  1. Armen RS, Schiller SM, Brooks CL, III. Steric and thermodynamic limits of design for the incorporation of large unnatural amino acids in aminoacyl-tRNA synthetase enzymes. Proteins. 2010;78(8):1926-38.

  2. Bostick DL, Brooks CL, III. Selective complexation of K+ and Na+ in simple polarizable ion-ligating systems. J Am Chem Soc. 2010;132(38):13185-7. PMCID: 3051181.

  3. Hills RD, Jr., Kathuria SV, Wallace LA, Day IJ, Brooks CL, III, Matthews CR. Topological frustration in beta alpha-repeat proteins: sequence diversity modulates the conserved folding mechanisms of alpha/beta/alpha sandwich proteins. J Mol Biol. 2010;398(2):332-50. PMCID: 2862464.

  4. Hirschi JS, Arora K, Brooks CL, III, Schramm VL. Conformational Dynamics in Human Purine Nucleoside Phosphorylase with Reactants and Transition-State Analogues (dagger). J Phys Chem B. 2010.

  5. May ER, Armen RS, Mannan AM, Brooks CL, III. The flexible C-terminal arm of the Lassa arenavirus Z-protein mediates interactions with multiple binding partners. Proteins. 2010;78(10):2251-64.

  6. Michino M, Chen J, Stevens RC, Brooks CL, III. FoldGPCR: structure prediction protocol for the transmembrane domain of G protein-coupled receptors from class A. Proteins. 2010;78(10):2189-201.

  7. Zimmermann J, Romesberg FE, Brooks CL, III, Thorpe IF. Molecular description of flexibility in an antibody combining site. J Phys Chem B. 2010;114(21):7359-70. PMCID: 2892760.

  8. Arthur E, Yesselman J, Brooks CL, III. Predicting Extreme pKa Shifts in Staphylococcal Nuclease Mutants with Constant pH Molecular Dynamics. Proteins. 2011;in the press.

  9. Bailor MH, Mustoe AM, Brooks CL, III, Al-Hashimi HM. Topological constraints: using RNA secondary structure to model 3D conformation, folding pathways, and dynamic adaptation. Curr Opin Struct Biol. 2011;21(3):296-305.

  10. Feng J, Walter NG, Brooks CL. Cooperative and Directional Folding of the preQ(1) Riboswitch Aptamer Domain. J Am Chem Soc. 2011;133(12):4196-9.

  11. Knight JL, Brooks CL, III. Applying efficient implicit nongeometric constraints in alchemical free energy simulations. J Comput Chem. 2011.

  12. Knight JL, Brooks CL, III. Surveying implicit solvent models for estimating small molecule absolute hydration free energies. J Comput Chem. 2011;32(13):2909-23. PMCID: 3142295.

  13. Knight JL, Brooks CL, III. Multisite λ Dynamics for Simulated Structure␣Activity Relationship Studies. J Chem Theor Comp. 2011;in the press.