The goals of this research are to develop computational tools to design enzyme catalysts for reactions not found in nature. Catalytic binding sites for several types of reactions will be designed, based upon both covalent and noncovalent catalytic mechanisms. Combinatorial exploration of potential side-chain catalytic groups, followed by quantum mechanical testing of optimum catalytic arrangements will lead to a hierarchy of potential catalytic sites. Our collaborators, David Baker and his group, will use the coordinates of the designed catalytic sites to predict sequences that will fold into a catalytic site with this geometry. QM and QM/MM methods will be tested and developed in our lab to predict which of the designed proteins are likely to be the best catalysts. The proteins will be synthesized by the Baker group with standard molecular biological techniques, and in collaboration we will test the catalytic activity and mechanisms of these new proteins. Emphasis is on the development of efficient methods for the prediction of effective protein catalysts, and these methods will be tested against known data on enzymes and mutants that have different catalytic proficiencies.

Public Health Relevance

During this grant period, we will develop and use the tools of computational chemistry to design novel enzymes. Our emphasis will be to demonstrate that we can do what has never been done before: design a functioning enzyme from scratch, starting with ideas about a catalytic site and ending with a fully functioning enzyme for a non-natural reaction. The initial target reactions will be of use in the synthesis of pharmaceutical targets and for the decomposition of a broad class of compounds utilized as pesticides and herbicides.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Gerratana, Barbara
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
Zip Code
Narayan, Alison R H; Jiménez-Osés, Gonzalo; Liu, Peng et al. (2015) Enzymatic hydroxylation of an unactivated methylene C-H bond guided by molecular dynamics simulations. Nat Chem 7:653-60
Hog, Daniel T; Huber, Florian M E; Jiménez-Osés, Gonzalo et al. (2015) Evolution of a Unified Strategy for Complex Sesterterpenoids: Progress toward Astellatol and the Total Synthesis of (-)-Nitidasin. Chemistry 21:13646-65
Noey, Elizabeth L; Tibrewal, Nidhi; Jiménez-Osés, Gonzalo et al. (2015) Origins of stereoselectivity in evolved ketoreductases. Proc Natl Acad Sci U S A 112:E7065-72
Osuna, Sílvia; Jiménez-Osés, Gonzalo; Noey, Elizabeth L et al. (2015) Molecular dynamics explorations of active site structure in designed and evolved enzymes. Acc Chem Res 48:1080-9
Numajiri, Yoshitaka; Jiménez-Osés, Gonzalo; Wang, Bo et al. (2015) Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation. Org Lett 17:1082-5
Tang, Weixin; Jiménez-Osés, Gonzalo; Houk, K N et al. (2015) Substrate control in stereoselective lanthionine biosynthesis. Nat Chem 7:57-64
Yang, Zhongyu; Jiménez-Osés, Gonzalo; López, Carlos J et al. (2014) Long-range distance measurements in proteins at physiological temperatures using saturation recovery EPR spectroscopy. J Am Chem Soc 136:15356-65
Jiménez-Osés, Gonzalo; Osuna, Sílvia; Gao, Xue et al. (2014) The role of distant mutations and allosteric regulation on LovD active site dynamics. Nat Chem Biol 10:431-6
Medina, Jose M; McMahon, Travis C; Jiménez-Osés, Gonzalo et al. (2014) Cycloadditions of cyclohexynes and cyclopentyne. J Am Chem Soc 136:14706-9
Gao, Xue; Jiang, Wei; Jiménez-Osés, Gonzalo et al. (2013) An iterative, bimodular nonribosomal peptide synthetase that converts anthranilate and tryptophan into tetracyclic asperlicins. Chem Biol 20:870-8

Showing the most recent 10 out of 20 publications