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Because we are interested in realistic simulations, our computer models tend to be too large and/or too complicated for manual electronic structure analysis. Therefore, we develop an artificially intelligent computer program that can mine, store and interpret electronic structure data from quantum chemistry calculations and come up with potentially interesting targets based upon case-based reasoning. A second method for identifying potentially interesting molecules is sampling a huge number of possible targets in a combinatorial computational approach. In practice, we want to combine the brute-force combinatorial sampling with some logic to save time and effort. Our goal is to teach the computer how to do this for us, so that we can go fishing while the work is being done without human interaction....
Cisplatin, a Pt(II)-based drug, is one of the most widely used and successful anticancer drugs. While much is known about the mechanism of its antitumor activity, we still do not understand fully what electronic features of the metal-complex are crucial for the interaction of cisplatin with its primary cellular target DNA. We are interested in deriving a new paradigm for rational drug design that attempts to reproduce and amplify the important electronic features promoting the antitumor activity with new reagents based on Pt(II) or completely different metals. A second focus is on Pt(IV)-complexes that have shown up to 800-fold higher antitumor activity in in vitro assays, but are presumably not redox stable in vivo. We study a number of Pt(IV) complexes to understand their redox chemistry and predict new compounds with higher stability. We are also interested in understanding in a more fundamental sense how DNA gets oxidized and how transition metals in general interact with DNA. Oxidative damage of DNA is believed to be one of the main events that leads to mutagenesis and often results in cancer. We try to understand how DNA behaves in an oxidative environment in general using computational methods.
Water oxidation is a key reaction that we must be able to control if the dream of artificial photosynthesis is ever to become reality. In the photosynthetic machinery of plants water is oxidized to give molecular dioxygen releasing four equivalents of protons and electrons. These electrons are then available for chemical transformations, such as activation of carbon dioxide. A few ruthenium and manganese compounds have been shown to promote the same catalysis, demonstrating that we could in principle copy nature in a technical setting. Unfortunately, none of these compounds are currently efficient enough for technological utilization and much work remains to be done to build a technology that will harness solar energy for chemical purposes. We are studying the electronic structure and reaction mechanism of these catalysts. The goal is to establish a molecular level understanding of the catalysis and derive design rules for making a better catalyst
Coupling classical molecular dynamics(MD) and quantum mechanics(QM) simulations is essential for constructing a complete molecular model for enzymatic reactions, while keeping the computational cost at a viable level. Our ability to study metalloproteins that often function as important enzymes or cause fatal diseases is currently limited because they cannot be included appropriately in a large-scale computer simulation. We are developing a discovery network that interfaces molecular dynamics, high-level quantum mechanics and combined quantum mechanics/molecular mechanics simulations to realistically model metalloprotein reactions. The main focus of our current work is on understanding how Alzheimer's disease progresses. It is believed that the destruction of brain cells is connected to the formation of a Cu-peptide aggregate. We are investigating mechanisms that might give rise to chemical agents causing cell death to assist the collective effort of developing a treatment for Alzheimer's disease.
"Diastereoselective Intermolecular Rhodium-Catalyzed [4+2+2] Carbocyclization Reactions: Computational and Experimental Evidence for the Intermediacy of a New Metallacycle Intermediate" Mu-Hyun Baik, Erich W. Baum, Matthew C. Burland and P. Andrew Evans, J. Am. Chem. Soc. 2005, 127, 1602.
"Electronic Structure of the Water-Oxidation Catalyst [(bpy)2(OHx)RuORu(OHy)(bpy)2]z+: Weak Coupling Between the Metal Centers is Preferred over Strong Coupling" Xiaofan Yang and Mu-Hyun Baik, J. Am. Chem. Soc. 2004, 126, 13222.
"Dioxygen Activation in Methane Monooxygenase: A Theoretical Study" Benjamin F. Gherman, Mu-Hyun Baik, Stephen J. Lippard and Richard A. Friesner, J. Am. Chem. Soc. 2004, 126, 2978.
"Theoretical Study of Cisplatin Binding to Purine Bases: Why Does Cisplatin Prefer Guanine over Adenine?" Mu-Hyun Baik, Richard A. Friesner and Stephen J. Lippard J. Am. Chem. Soc. 2003, 125, 14082.
"Peripheral Heme Substituents control the Hydrogen-Atom Abstraction Chemistry in Cytochrome P450" Victor Guallar, Mu-Hyun Baik, Stephen J. Lippard and Richard A. Friesner Proc. Natl. Acad. Sci. USA 2003, 100, 6998.
"Mechanistic Studies on the Hydroxylation of Methane by Methane Monooxygenase" Mu-Hyun Baik, Richard A. Friesner and Stephen J. Lippard Chem. Rev. 2003, 103, 2385.
"Computing Redox-Potentials in Solution: DFT as A Tool for Rational Design of Redox Agents" with R. A. Friesner, J. Phys. Chem. A, 106, 7407 (2002).
"Theoretical Study on the Stability of N-Glycosyl Bonds: Why does N7-Platination not Promote Depurination?" with R. A. Friesner and S. J. Lippard, J. Am. Chem. Soc., 124, 4495 (2002).
"DFT Study of Redox Pairs. 2. Influence of Solvation and Ion Pair Formation on the Redox Behavior of Cyclooctatetraene and Nitrobenzene" with C. K. Schauer and T. Ziegler, J. Am. Chem. Soc., 124, 11167 (2002).
"Using Density Functional Theory To Design DNA Base Analogues with Low Oxidation Potentials" with Wt. Yang, H. H. Thorp and others, J. Phys. Chem. B, 105, 6437 (2001).
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