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.

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Efficient Simulation Method for Polarizable Protein Force Fields: Application to the Simulation of BPTI in Liquid Water, Edward Harder, Byungchan Kim, Richard A. Friesner and B.J. Berne, J. Chem. Theory and Comput.  1, 169-180 (2005)

Substrate Hydroxylation in Methane Monooxygenase:  Quantitative Modeling via Mixed Quantum Mechanics/Molecular Mechanics Techniques, Gherman, Benjamin F., Stephen J. Lippard and Richard A. Friesner, J. Am. Chem. Soc., 127, 3, 1025 -1037 (2005)

Ab Initio Quantum Chemical and Mixed Quantum Mechanics/Molecular Mechanics (QM/MM) Methods for Studying Enzymatic Catalysis, Friesner, Richard A. and Victor Guallar, Ann. Rev. Phys. Chem., 56, 389-427 (2005)    

Pseudospectral Local Second Order Miller-Plesset Methods for Computation of Hydrogen Bonding Energies of Molecular Pairs, Kaminski, George A. Jon Maple, Robert B. Murphy, Dale A. Braden, and Richard A. Friesner, J. Chem. Theory and Comput., 1, 248-254 (2005)

Importance of Accurate Charges in Molecular Docking:  Quantum Mechanical/Molecular Mechanical (QM/MM) Approach, Cho, Art E., Victor Guallar, Bruce J. Berne and Richard Friesner, J. Comp. Chem., 26, 9, 915-931 (2005)

Chemical Theory & Computations Special Feature: Ab Initio Quantum Chemistry: Methodology and Applications, Friesner, Richard A., PNAS, 102, 19, 6648-6653 (2005)

Structural and Chemical Trends in Doped Silicon Nanocrystals: First-Principles Calculations, Zhou, Z. Y.; M. L. Steigerwald, R.A. Friesner, L. Brus, M.S. Hybertsen, Phys. Rev. B, 71, 24, 245308 (2005)

Molecular (Hyper) Polarizabilities Computed by Pseudospectral Methods, Cao, Yixiang, Richard A. Friesner, J Chem. Phys. 122, 10. 104102 (2005)

Structure & Dynamics of the Solvation of Bovine Pancreatic Trypsin Inhibitor in Explicit Water:  A Comparative Study of the Effects of Solvent and Protein Polarizability, Kim, Byungchan, Tom Young, Edward Harder, Richard A. Friesner, and Bruce J. Berne, J. Phys. Chem. B. 109, 34, 16529-16538 (2005)

Replica Exchange with Solute Tempering:  A Method for Sampling Biological Systems in Explicit Water, Pu Liu, Byungchan Kim, Richard A. Friesner, and B. J. Berne, PNAS, 102, 39, 13749-13754 (2005)

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