This action funds an NSF Minority Postdoctoral Research Fellowship for FY 2009 and is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). The fellowship supports a research and training plan in a host laboratory for the Fellow who also presents a plan to broaden participation in biology. The title of the research and training plan for this fellowship to Lucas Nivon is "Computational design of new enzymes: catalyzing carbon-carbon bond formation in bi-molecular reactions." This research is being conducted at The University of Washington under the sponsorship of Dr. David Baker.
Enzymes are responsible for the wide variety of metabolic functions in living organisms but natural enzymes cannot catalyze most commercially important synthetic reactions. This research tests current understanding of enzyme function by using chemical principles to computationally design new enzymes for non-natural reactions. Novel enzymes have been successfully produced for a retro-Aldol (RA) addition and the Kemp elimination by using new algorithms to search for appropriate active sites and to design atomically-accurate pockets to bind the transition states of particular chemical reactions. These reactions are uni-molecular. This project is tackling bimolecular, bond-forming reactions by studying 2 reactions closely related to the RA (Michael addition and forward Aldol addition) by re-designing RA enzymes for these bimolecular reactions. Additionally under study is the Morita-Bayliss-Hillman (MBH) reaction, which is widely applied in modern syntheses, but is nonexistent in nature, to ask whether enzymes can catalyze a reaction previously known only to synthetic chemistry.
Training plans include learning computational methods of protein design and the biochemical skills necessary to perform a wide range of enzymatic assays and large-scale enzyme purifications. By using established theories of enzyme function to design new proteins this project will critically test those theories and perhaps reveal new basic principles of enzyme function. Outside of pure biochemistry this work is useful for biotechnology and medicine, allowing the design of new enzymes for industrial applications or for use as enzyme drugs or diagnostics. Broader impacts also include educational outreach to students, especially from under-represented groups.