A robust suite of tools will be developed and validated for the accurate prediction of catalytic proficiencies of enzymes through combined quantum mechanical-molecular mechanical computations of unprecedented accuracy. Accurate QM potentials will be computed using local correlation methods [LMP2, L-CCSD, L- CCSD(TO)] and through the use of a new composite ab initio approach based on the extrapolation of local coupled cluster energies to the complete basis set limit. This extrapolation procedure will be calibrated using a set of small molecules, to allow for the explicit comparison of extrapolated local correlation energies with results from established extrapolation approaches applied to conventional ab initio methods. The proposed QM/MM approaches will be validated and refined through comparison with an extensive set of experimentally determined kinetic data for wild type and mutated chorismate mutase and subtilisin proteins. DFT/MM methods will also be benchmarked against this experimental test set, utilizing new DFT functions that should offer substantial improvements to the venerable B3LYP. Once validated and fine- tuned through extensive comparisons with experimental data, these computational tools will be utilized in the ranking of novel enzyme designs to catalyze synthetically useful aldol condensations. Further, the QM/MM methods developed will allow for definitive quantitative studies of enzyme catalysis, including definitive studies of ODCase and other enzymes for which the catalytic mechanism is still unsettled. Computational tools to accurately model the catalytic efficacy of enzymes will be developed by combining quantum mechanical and classical mechanical methods. The immediate applications of these powerful computational tools will be in the design of new enzymes that catalyze reactions not found in nature. Such enzymes will be instrumental in novel synthetic pathways as well as for the development of enzyme-based therapeutics. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04B-N (20))
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Flicker, Paula F
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Wheeler, Steven E; McNeil, Anne J; Muller, Peter et al. (2010) Probing substituent effects in aryl-aryl interactions using stereoselective Diels-Alder cycloadditions. J Am Chem Soc 132:3304-11
Wheeler, Steven E; Houk, K N (2010) Are anion/pi interactions actually a case of simple charge-dipole interactions? J Phys Chem A 114:8658-64
Wheeler, Steven E; Houk, K N (2010) Integration Grid Errors for Meta-GGA-Predicted Reaction Energies: Origin of Grid Errors for the M06 Suite of Functionals. J Chem Theory Comput 6:395-404
Hargis, Jacqueline C; Schaefer 3rd, Henry F; Houk, K N et al. (2010) Noncovalent interactions of a benzo[a]pyrene diol epoxide with DNA base pairs: insight into the formation of adducts of (+)-BaP DE-2 with DNA. J Phys Chem A 114:2038-44
Wheeler, Steven E; Houk, K N (2009) Origin of Substituent Effects in Edge-to-Face Aryl-Aryl Interactions. Mol Phys 107:749-760
Wheeler, Steven E; Houk, K N (2009) Substituent effects in cation/pi interactions and electrostatic potentials above the centers of substituted benzenes are due primarily to through-space effects of the substituents. J Am Chem Soc 131:3126-7
Wheeler, Steven E; Houk, Kendall N; Schleyer, Paul v R et al. (2009) A hierarchy of homodesmotic reactions for thermochemistry. J Am Chem Soc 131:2547-60
Wheeler, Steven E; Houk, K N (2009) Through-Space Effects of Substituents Dominate Molecular Electrostatic Potentials of Substituted Arenes. J Chem Theory Comput 5:2301-2312
Wheeler, Steven E; Moran, Antonio; Pieniazek, Susan N et al. (2009) Accurate reaction enthalpies and sources of error in DFT thermochemistry for aldol, Mannich, and alpha-aminoxylation reactions. J Phys Chem A 113:10376-84
Ess, Daniel H; Wheeler, Steven E; Iafe, Robert G et al. (2008) Bifurcations on potential energy surfaces of organic reactions. Angew Chem Int Ed Engl 47:7592-601

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