Mu-Hyun (Mookie) Baik

Faculty Title

Assistant Professor of Informatics

Research Statement

My research centers on examining complex chemical reactions using large-scale quantum chemical models and developing novel methods of extracting chemical information from these calculations. The goal is to develop an artificial expert system that can be used to efficiently search for novel and rational design strategies for better anticancer drugs, robust industrial catalysts or new materials and to discover the mode of action of metalloenzymes.

Our group is interested in understanding the electronic structure of molecules that either do something useful or something interesting. We focus mainly, but not exclusively, on transition metal containing systems. Using quantum chemical methods to first derive a detailed understanding of what makes the molecule behave the way it does, we ask what we need to do to control its chemical behavior. We are also interested in large-scale simulations of metalloenzymes to understand how they work and identify potential ways of replicating their reactivity in industrial settings with biomimetic complexes. Most of our research is done in close collaboration with experimental chemists who help us refine our computational models and predictions.

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 using 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.

Transition metal-based catalysts are expected to become crucial in the future with new generations of experimental catalysts currently waiting to reach maturity. One of our catalysis projects is directed towards improving a new class of olefin polymerization catalysts based on Ni(II) and Pd(II) complexes. These catalysts, developed by Professor Brookhart (UNC), are expected to play a major role in the future for making new polymer-based materials but are currently too expensive to be used in an industrial scale. In collaboration with the Brookhart lab, we investigate the catalytic reaction mechanism and attempt to find a new catalyst that is more robust and thermally more stable.

Xanthine oxidases form a family of Mo-based metalloenzymes that can insert an oxygen between a C-H bond to give C-OH at ambient conditions. This is a remarkable reaction because C-H bonds are usually very inert, that is difficult to do chemistry on. We use a large scale computational model to simulate the enzymatic reaction. We want to understand how nature uses the Mo-center for carrying out such a difficult reaction under mild conditions and explore how we could mimic this enzyme with a simple inorganic system. Nature has a number of even more powerful oxygenases in stock for us, such as methane monooxygenase (MMO) that can activate the most inert C-H bond of all found in methane. However, xanthine oxidases are special because they do not depend on an external source for electrons, while MMO for example consumes one equivalent of NADH for each conversion cycle. We want to understand how the electronic structures of these metalloenzymes differ from each other and suggest ways of making the Mo-based more powerful oxidants.

Select Publications

• “Mechanistic Studies on the Hydroxylation of Methane by Methane Monooxygenase”, Mu-Hyun Baik, Martin Newcomb, Richard A. Friesner and Stephen J. Lippard, Chemical Reviews 2003, 103, 2385-2419 (2003)
• “Peripheral Heme Substituents control the Hydrogen-Atom Abstraction Chemistry in Cytochromes P450” with V. Guallar, S. J. Lippard and R. A. Friesner, Proceedings of the National Academy of Sciences - USA, 100, 6998 (2003).
• “Hydroxylation of Methane by Non-Heme Diiron Enzymes. A Molecular Orbital Analysis of the C-H Bond Activation by Reactive Intermediate Q” with B. F. Gherman, R. A. Friesner and S. J. Lippard, Journal of the American Chemical Society, 124, 14608 (2002).
• “Computing Redox-Potentials in Solution: DFT as A Tool for Rational Design of Redox Agents” with R. A. Friesner, Journal of Physical Chemistry 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, Journal of the American Chemical Society, 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, Journal of the American Chemical Society, 124, 11167 (2002).
• “Using Density Functional Theory To Design DNA Base Analogues with Low Oxidation Potentials” with Wt. Yang, H. H. Thorp and others, Journal of Physical Chemistry B, 105, 6437 (2001).
• Full publication list

More Information

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Research Links

• Informatics Research Areas