Understanding the forces that determine the structure 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 use statistical mechanics, molecular simulations, statistical modeling, and quantum chemistry.
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.
Interpreting experimental results at more microscopic levels is fueled by the development and investigation of theoretical models for the processes of interest that range form atomic level detail to more coarse-grained molecular representations. 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, and computational grids. Each of the objectives and techniques mentioned represents an ongoing area of development within our research program.
Bostick, DL & Brooks, CL, III. Deprotonation by Dehydration: The Origin of Ammonium Sensing in the AmtB Channel. PLoS Comput Biol. 3, e22 (2007).
Bostick, DL & Brooks, CL, III. Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state. Proc Natl Acad Sci, USA. 104, 9260-5 (2007).
Bu, L, Im, W & Brooks, CL, III. Membrane assembly of simple helix homo-oligomers studied via molecular dynamics simulations. Biophys J. 92, 854-63 (2007).
Chen, J & Brooks, CL, III. Critical importance of length-scale dependence in implicit modeling of hydrophobic interactions. J Am Chem Soc. 129, 2444-5 (2007).
Hills, RD, Jr. & Brooks, CL, III. Hydrophobic cooperativity as a mechanism for amyloid nucleation. J Mol Biol. 368, 894-901 (2007).
Khandogin, J & Brooks, CL, III. Linking folding with aggregation in Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci, USA. 104, 16880-5 (2007).
Khavrutskii, IV, Price, DJ, Lee, J & Brooks, CL, III. Conformational change of the methionine 20 loop of Escherichia coli dihydrofolate reductase modulates pKa of the bound dihydrofolate. Protein Sci. 16, 1087-100 (2007).
Nguyen, HD, Reddy, VS & Brooks, CL, III. Deciphering the kinetic mechanism of spontaneous self-assembly of icosahedral capsids. Nano Lett. 7, 338-44 (2007).
Thorpe, IF & Brooks, CL, III. Molecular evolution of affinity and flexibility in the immune system. Proc Natl Acad Sci, USA. 104, 8821-6 (2007).
Chen, J, Brooks, CL, III & Scheraga, HA. Revisiting the carboxylic Acid dimers in aqueous solution: interplay of hydrogen bonding, hydrophobic interactions, and entropy. J Phys Chem B. 112, 242-9 (2008).
Olson, MA, Feig, M & Brooks, CL, III. Prediction of protein loop conformations using multiscale modeling methods with physical energy scoring functions. Proteins. in the press (2007).
Bu, L & Brooks, CL, III. De Novo Prediction of the Structures of M. Tuberculosis Membrane Proteins. J Am Chem Soc. in the press (2008).
Mannige, RV & Brooks, CL, III. On the tilable nature of virus capsids and the role of topological constraints in natural capsid design. Phys Rev E. in the press (2008).