Award Abstract #0715448
Protein dynamics and hydrogen tunneling in enzyme catalysis

NSF Org:	CHE Division of Chemistry
Initial Amendment Date:	August 3, 2007
Latest Amendment Date:	January 7, 2009
Award Number:	0715448
Award Instrument:	Standard Grant
Program Manager:	Charles D. Pibel CHE Division of Chemistry MPS Directorate for Mathematical & Physical Sciences
Start Date:	August 15, 2007
Expires:	July 31, 2011 (Estimated)
Awarded Amount to Date:	$565932
Investigator(s):	Amnon Kohen amnon-kohen@uiowa.edu (Principal Investigator)
Sponsor:	University of Iowa 2 GILMORE HALL IOWA CITY, IA 52242 319/335-2123
NSF Program(s):	STRUCTURE AND REACTIVITY, BIOMOLECULAR SYSTEMS
Field Application(s):
Program Reference Code(s):	OTHR, 0000
Program Element Code(s):	1960, 1144

ABSTRACT

In this award, funded by the Experimental Physical Chemistry Program of the Chemistry Division and the Molecular Biochemistry Program of the Molecular and Cellular Biosciences Division of the Biology Directorate, Prof. Amnon Kohen. of the University of Iowa and his graduate and undergraduate student colleagues will pursue studies aimed at developing a better understanding of how enzymes activate covalent bonds. The ultimate goal of this research is to understand how enzyme dynamics influence reactivity. Specifically, they will study three model systems: Dihydrofolate reductase, alcohol dehydrogenase and thymidylate synthase. Their approach to studying these enzymes is through making specific mutations to the enzyme that subtly change the enzyme structure in known ways and correlating these structural changes with changes in reactivity.

Enzymes are ubiquitous in biology, medicine and commerce. The ultimate aims of research like that of Prof. Kohen and his group is to gain a mechanistic insight into how biological systems do important chemistries. This will shed light on the role of evolution in refining bond activation, the role of quantum phenomena (light atom tunneling) in biology, and will move us towards a better understanding of Global Structure-Dynamics-Function relationships in enzymes, which will have a broad impact in areas of society where the ability to design enzymes to work in useful ways is important. Besides the broader scientific impacts of this work, Prof. Kohen will continue to recruit, mentor and educate a diverse group of young scientists in science that lies at the interface of the physical and biological sciences.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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2. Bandaria, J., Dutta, S., Hill, S., Kohen, A., and Cheatum, C..  "Fast Enzyme Dynamics at the Active Site of Formate Dehydrogenase,"  J. Am. Chem. Soc.,  v.120,  2008,  p. 22.

4. Hong, B., Maley, F, and Kohen, A..  "Role of Y94 in Proton and Hydride Transfers Catalyzed by Thymidylate Synthase,"  Biochemistry,  v.46,  2007,  p. 14188.

6. Kanaan, N., Martí, S., Moliner, V., and Kohen, A..  "A QM/MM Study of the catalytic mechanism of the thymidylate synthase,"  Biochemistry,  v.46,  2007,  p. 3704.

Atsushi Yahashiri, Elizabeth E. Howell, and Amnon Kohen.  "Tuning of the H-Transfer Coordinate in Primitive versus Well-Evolved,"  ChemPhysChem,  v.9,  2008,  p. 980.


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