研究领域

Biological Chemistry/Theoretical Chemistry

The research in my group is focused on the following major areas: Development and application of novel methods for ab initio electronic structure calculations, including mixed quantum mechanics/molecular mechanics (QM/MM) methods; Development of a new generation of molecular mechanics force fields, including explicit incorporation of polarizability; Investigation and improvement of continuum treatments of aqueous solvation; Computational models and algorithms for protein structure prediction; Modeling of protein-active site chemistry using quantum chemical and QM/MM methods; Electron transfer theory; and Quantum chemical modeling of the interactions of small molecules with surfaces and nanostructures. Projects typically include a combination of analytical theory, algorithm and software development, and applications of new methods to biology or materials science. Some highlights of our recent research are as follows: We have developed accurate quantum chemical models for intermediates and transition states of the catalytic cycle of the enzyme methane monooxygenase (MMO). MMO is a bacterial enzyme, containing a di-iron core, that catalyzes the conversion methane and dioxygen into methanol. Our density functional theory (DFT) calculations use approximately 100 atoms to describe the enzyme-active site and are in good agreement with experimentally available structures, energies, spin states, and other observable properties. Inclusion of the second coordination shell around the two metal atoms is essential in understanding how the protein controls the states in the catalytic cycle. We have developed a QM/MM methodology specifically designed to model protein-active sites. The method has been extensively benchmarked against fully quantum chemical data for a series of peptides. We are currently applying the method to a variety of protein-active site modeling problems, including cytochrome P450, beta-lactamases, and penicillin-binding proteins, and reversible oxygen binding in hemerythrin. We have developed an automated methodology for constructing a polarizable force field for arbitrary organic molecules based on ab initio quantum chemical calculations. We have applied this approach to small-molecule gas phase and condensed phase calculations and, more recently, have assembled a complete protein force field. We have entered the most recent protein structure prediction contest (CASP4) and demonstrated considerable success in carrying out fold recognition for homologous proteins with low sequence identity. We are also engaged in obtaining accurate alignments for low sequence identity homologs and in performing high resolution structural refinement for homology modeling.

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Ko, Chaehyuk, David K. Malick, Dale A. Braden, Richard A. Friesner and Todd J. Martinez, Pseudospectral time-dependent density functional theory, J. Chem. Phys., 128, 10, 104103, (2008). Knight, Jennifer L., Zhiyong Zhou, Emilio Gallicchio, Daniel M. Himmel, Richard A. Friesner, Eddy Arnold, and Ronald M. Levy, Exploring structural variability in X-ray crystallographic models using protein local optimization by torsion-angle sampling, Acta Crystallographica Sect. D, Biological Crystallography, 64, 4, 383-396 (2008). Sellers, Benjamin D., Kai Zhu, Suwen Zhao, Richard A. Friesner, Matthew P. Jacobson, Towards better refinement of comparative models: Predicting loops in inexact environments, Proteins, Structure, Function and Bioinformatics, 72, 3, 959-971 (2008). Maragakis, Paul, Kresten Lindorff-larsen, Michael P. Eastwood, Ron O. Drorr, John L. Klepeis, Isaiah T. Arkin, Morten O. Jensen, Huafeng Xu, Nikola Trbovic, Richard A. Friesner, Arther G. Palmer III, and David E. Shaw, Microsecond molecular dynamics simulation shows effect of slow loop dynamics on backbone amide order parameters of proteins, J. Phys. Chem. B, 112, 19, 6156-6158 (2008). Trbovic, Nikola, Byungchan Kim, Richard A. Friesner, and Arthur G. Palmer, III, Structural Analysis of Protein Dynamics by MD Simulations and NMR Spin Relaxation, Proteins, Structure, Function, and Bioinformatics, 71, 2, 684-694 (2008). Felts, Anthony, K., Emilio Gallicchio, Dmitriy Chekmarev, Kristina A. Paris, Richard A. Friesner, and Ronald M. Levy, Prediction of Protein Loop Conformations Using the AGBNP Implicit Solvent Model and Torsion Angle Sampling, J. Chem. Theo. Comput., 4, 5, 855-868 (2008). Rinaldo, David, Li Tian, Jeremy N. Harvey, and Richard A. Friesner, Density Functional Localized Orbital Corrections for Transition Metals, J. Chem. Phys., 129, 164108-164123 (2008). Goldfeld, Dahlia A., Arteum D. Bochevarov, and Richard A. Friesner, Localized orbital corrections applied to thermochemical errors in density functional theory: The role of basis set and application to molecular reactions, J. Chem. Phys., 129, 21, 214105 (2008). "The Densities Produced by the Density Functional Theory: Comparison to Full Configuration Interaction" Arteum D. Bochevarov, Richard A. Friesner, J. Chem. Phys. 128, 3, 034102 (2008) "Density Functional Localized Orbital Corrections for Transition Metals" David Rinaldo, Li Tian; Jeremy N. Harvey, Richard A. Friesner, J. Chem. Phys. 129, 164108-164123 (2008) "Exploring Structural Variability in X-ray Crystallographic Models using Protein Local Optimization by Torsion-Angle Sampling" Jennifer L. Knight, Zhiyong Zhou, Emilio Gallicchio, Daniel M. Himmel, Richard A. Friesner, Eddy Arnold, Ronald M. Levy, Acta Crystallographica Sect. D, Biological Crystallography 64, 4, 383-396 (2008) "Localized Orbital Corrections Applied to Thermochemical Errors in Density Functional Theory: The Role of Basis Set and Application to Molecular Reactions" Dahlia A. Goldfeld, Arteum D. Bochevarov, Richard A. Friesner, J. Chem. Phys. 129, 21, 214105 (2008) "Microsecond Molecular Dynamics Simulation Shows Effect of Slow Loop Dynamics on Backbone Amide Order Parameters of Proteins" Paul Maragakis, Kresten Lindorff-Larsen, Michael P. Eastwood, Ron O. Drorr, John L. Klepeis, Isaiah T. Arkin, Morten O. Jensen, Huafeng Xu, Nikola Trbovic, Richard A. Friesner, Arther G. Palmer III, David E. Shaw, J. Phys. Chem. B 112, 19, 6156-6158 (2008) "Role of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand Binding" Robert Abel, Tom Young, Ramy Farid, Bruce J. Berne, Richard A. Friesner, J. Med. Chem. 130, 9, 2817-2831 (2008) "Prediction of Protein Loop Conformations Using the AGBNP Implicit Solvent Model and Torsion Angle Sampling" Anthony K. Felts, Emilio Gallicchio, Dmitriy Chekmarev, Kristina A. Paris, Richard A. Friesner, Ronald M. Levy, J. Chem. Theo. Comput. 4, 5, 855-868 (2008) "Pseudospectral Time-Dependent Density Functional Theory" Chaehyuk Ko, David K. Malick, Dale A. Braden, Richard A. Friesner, Todd J. Martinez, J. Chem. Phys. 128, 10, 104103 (2008) "Structural Analysis of Protein Dynamics by MD Simulations and NMR Spin Relaxation" Nikola Trbovic, Byungchan Kim, Richard A. Friesner, Arthur G. Palmer, III, Proteins: Structure, Function, and Bioinformatics 71, 2, 684-694 (2008) "Towards Better Refinement of Comparative Models: Predicting Loops in Inexact Environments" Benjamin D. Sellers, Kai Zhu, Suwen Zhao, Richard A. Friesner, Matthew P. Jacobson, Proteins: Structure, Function and Bioinformatics 72, 3, 959-971 (2008)