Department of Chemistry, Columbia University
3000 Broadway, mail code 3110
New York, NY 10027

work:+1 212-854-7606

fax:+1 212-854-7454

rich@chem.columbia.edu

Research SummaryThe 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:

1. 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.
2. 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.
3. 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.
4. 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.

Back to Top

“Structural Analysis of Protein Dynamics by MD Simulations and NMR Spin Relaxation”  Nikola Trbovic, Byungchan Kim, Richard A. Friesner, and Arthur G. Palmer, III, Proteins, Structure, Function, and Bioinformatics, in press (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, in press (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, and Ronald M. Levy, Acta Crystallographica Sect. D, Biological Crystallography 64, 4, 383-396 (2008)

“Pseudospectral Time-Dependent Density Functional Theory” Chaehyuk Ko, David K. Malick, Dale A. Braden, Richard A. Friesner, and Todd J. Martinez, J. Chem. Phys. 128, 10, 104103 (2008)

“The Densities Produced by the Density Functional Theory: Comparison to Full Configuration Interaction” Arteum D. Bochevarov, and Richard A. Friesner, J. Chem. Phys. 128, 3, 034102 (2008)

“Role of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand Binding” Robert Abel, Tom Young, Ramy Farid, Bruce J. Berne, and Richard A. Friesner, J. Med. Chem. 130, 9, 2817-2831 (2008)

“Improved Methods for Side Chain and Loop Predictions via the Protein Local Optimization Program: Variable Dielectric Model for Implicitly Improving the Treatment of Polarization Effects” Kai Zhu, Michael Shirts, Richard Friesner, J. Chem. Theor. Comput. 3, 6, 2108-2119 (2007)

“Comparative Performance of Several Flexible Docking Programs and Scoring Functions: Enrichment Studies for a Diverse Set of Pharmaceutically Relevant Targets” Zhiyong Zhou, Anthony K. Felts, Richard A. Friesner, and Ronald M. Levy, J. Chem. Inf. Model. 47, 4, 1599-1608 (2007)

“Replica Exchange with Solute Tempering: Efficiency in Large Scale Systems” Xuhui Huang, Morten Hagen, Byuncghan Kim, Richard A. Friesner, Ruhong Zhou, and Bruce J. Berne, J. Phys. Chem. B111, 19, 5405-5410 (2007)

Back to Top