Houk Research Group
Individual Research Projects
Research
The Houk group solves problems in organic and bio-organic chemistry using theoretical and computational methods and programs. Some of the group members are also involved in experimental research to test theoretical predictions and to develop new reactions, reagents, and catalysts which have been designed from theoretical investigations.
Description of Research Subgroups
INSIDE-OUT DESIGN OF NEW ENZYMES
We are involved in a collaboration with David Baker of the University of Washington, Department of Biochemistry. This project involves a completely general and unique start-to-finish protocol for rapid designing novel enzyme catalysts for any desired chemical reactions using naturally occurring or de novo designed protein scaffolds.

We first build catalytic sites unique catalytic site based upon chemical precedent and quantum mechanical calculations, followed by construction of a new stable protein that folds in such a way so as to produce the side-chain functionality appropriately oriented and in the proper environment to constitute the catalytic site. Recent publications in Science (707) and Nature describe initial successes.
UNDERSTANDING AND DESIGN OF STEREOSELECTIVE REACTIONS AND CATALYSTS
We use computational methods to learn the origins of stereoselectivity in synthetically useful reactions. This information, and quantitative calculations are used to design new reactions, reagents, and catalysts. Our goals are to understand stereoselectivity, to make predictions, and to devise and execute experimental tests of these predictions.

Christophe Allemann, Ruth Gordillo, Fernando R. Clemente, Paul Ha-Yeon Cheong, and K. N. Houk: "Theory of Asymmetric Organocatalysis of Aldol and Related Reactions: Rationalizations and Predictions," Acc. Chem. Res. 2004, 37, 558-569.
PERICYCLIC REACTION MECHANISMS, RATES, AND DYNAMICS
We use theory and computational methods to explore the transition states of pericyclic reactions, some of the most significant reactions of organic chemistry. We explore the mechanisms of cycloadditions, electrocyclizations, sigmatropic shifts, cheletropic reactions, and related processes. We are developing a general theory of substituent effects on rates and stereoselectivities of these reactions.

Kelli S. Khuong, Chris M. Beaudry, Dirk Trauner, and K. N. Houk: "Dienophile Twisting and Substituent Effects Influence Reaction Rates of Intramolecular Diels-Alder Cycloadditions: A DFT Study," J. Am. Chem. Soc. 2005, 127, 3688-3689.
BENCHMARKING COMPUTATIONAL METHODS FOR KINETICS AND THERMODYNAMICS OF PERICYCLIC REACTIONS
Pericyclic reactions are utilized in the syntheses of complex target molecules. The ability to compute rates and equilibrium constants accurately allows the prediction of the viability of proposed synthetic routes and/or the design of successful alternatives. Current high-accuracy computational methods can predict energies within 1 kcal/mol of experiments. However, those calculations require massive computational resources, and the system size that can be treated is very limited and is usually not applicable to real systems. The goal of this research is to find optimal methodologies for the study of pericyclic reactions. A variety of computational methods are being used to study pericyclic reactions for which accurate experimental data are available. This will allow us to find methods that provide the same level of accuracy as the most computationally expensive ones but that are also fast enough to be of general and routine applicability in pericyclic reactions.
Figure 1. Computed activation enthalpies (kcal/mol) for a series of model pericyclic reactions.
EXPLORING THE ORIGINS OF ENZYME CATALYSIS AND ANOMALOUS HIGH AFFINITY BINDERS
Enzymes are exceptional catalysts with average 22 kcal/mol and maximum 38 kcal/mol binding energies toward transition states.1 Such strong binding could not be accounted for solely by noncovalent interactions proposed by Pauling and others, such as hydrogen bonds, electrostatics, van der Waals, etc. Those factors can contribute only up to 15 kcal/mol for binding. We have proposed that most enzymes achieve over 1011 M-1 proficiency by full or partial covalent bond formation to the reacting substrate in the transition state, involving a change in chemical mechanism from that occurring in the uncatalyzed reaction in aqueous solution. Intermediates covalently bound to the enzyme or cofactor, proton transfer (general acid/base catalysis and low-barrier hydrogen bonds) occurring in the transition state, and bonding to metal cations in the transition state all fall into the category of covalent catalysis.2

Using our insights about covalent catalysis, we explore the origins of proficient enzyme catalysis and selectivity, including ODCase, aldolase, lipase, protease, NO synthase, etc. by modeling theozymes - an array of functional groups necessary for catalysis3 - with density functional theory. The goal is to understand how covalent and noncovalent interactions provide catalysis at a molecular level. We also examine the ultra scale binding of biotin and femtomolar antibodies with theozyme modeling in order to rationalize how noncovalent binding greater than 15 kcal/mol is feasible in these few examples.
1. Houk, K. N.; Leach, A. G.; Kim, S. P.; Zhang, X.: "Binding Affinities of Host-Guest, Protein-Ligand, and Protein-Transition-State Complexes," Angew. Chem. Int. Ed. 2003, 42, 4872-4897.
2. Zhang, X.: Houk, K. N.: "Why Enzymes Are Proficient Catalysts: Beyond the Pauling Paradigm," Acc. Chem. Res. 2005, ASAP.
3. Tantillo, D. J.; Chen, J.; Houk, K. N.: "Theozyme and Compuzymes: Theoretical Models for Biological Catalysis," Curr. Opin. Chem. Biol. 1998, 2, 743-750.
REACTIVE INTERMEDIATES IN BIOLOGY AND THE ATMOSPHERE
We use theoretical methods to explore the reactions undergone by neurotransmitters like NO and the functional equivalents such as RSNOs and NO precursors under various conditions. We learn how nitrogen and sulfur oxides react in biological systems and the atmosphere. We explore the roles of dynamics, entropy, solvation, and tunneling on the very rapid reactions of excited states, carbenes, singlet oxygen, radicals, and other reactive intermediates.

Michael D. Bartberger, Wei Liu, Eleonora Ford, Katrina M. Miranda, Christopher Switzer, Jon M. Fukuto, Patrick J. Farmer, David A. Wink, and Kendall N. Houk: "The Reduction of Potential of Nitric Oxide (NO) and its Importance to NO Biochemistry," Proc. Natl. Acad. Sci. USA 2002, 99, 10958-10963.
STRUCTURES AND PROPERTIES OF ORGANIC MATERIALS
Polycyclic aromatic compounds have shown great promise for use in organic electronic materials. In particular, thin film transistors of pentacene have been shown to exhibit charge carrier mobilities comparable to silicon. However, marketable devices based on pentacene have not been realized due to the ease with which pentacene is photooxidized. The mechanism of photooxidation is believed to proceed via photostimulated electron transfer to oxygen, leading to other products and the loss of any desirable electronic properties, although photooxidation via energy transfer to form singlet oxygen is also reasonable.5 A greater understanding of the mechanism may lead to the development of substituted pentacenes that overcome the stability problem.
1. Norton, J. E.; Houk, K. N. J. Am. Chem. Soc. 2005, 127, 4162-4163.
2. Lu, J.; Ho, D. M.; Vogelaar, N. J.; Kraml, C. M.; Pascal, R. A., Jr. J. Am. Chem. Soc. 2004, 126, 11168-11169.
3. Houk, K. N.; Lee, P. S.; Nendel, M. J. Org. Chem. 2001, 66, 5517-5521.
4. Bendikov, M.; Duong, H. M.; Starkey, K.; Houk, K. N.; Carter, E. A.; Wudl, F. J. Am. Chem. Soc. 2004, 126, 7416-7417.
5. Maliakal, A.; Raghavachari, K.; Katz, H.; Chandross, E.; Siegrist, T. Chem Mater. 2004, 16, 4980-4986.
6. Anthony, J. E.; Brooks,J. S.; Eaton, D. L.; Parkin, S. R. J. Am. Chem. Soc. 2001, 123, 9482-9483.
GATING IN HOST-GUEST COMPLEXES
We have discovered that conformational processes of host molecules can control the stabilities of host-guest complexes. We use theory to design gated cavitands that have a movable lid that will bind a wide range of small guest molecules, and release them only upon gate opening by a conformational change induced by heat, photochemistry, or redox processes. We undertake the synthesis and experimental studies of such controlled release container molecules.
K. N. Houk, Kensuke Nakamura, Chimin Sheu, and Amy E. Keating: "Gating as a Control Element in Constrictive Binding and Guest Release by Hemicarcerands," Science 1996, 273, 627-629.
Contact Houk | Contact Web Master
University of California, Los Angeles
Department of Chemistry and Biochemistry
607 Charles E. Young Drive East
Box 951569
Los Angeles, CA 90095-1569
Phone: (310) 206-0515
Fax: (310) 206-1843
Kendall N. Houk

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Last Modified:
May 5, 2008