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Glimpses into the mechanisms of RNA catalysis revealed by molecular simulations

Recent research from the group of Professor Darrin York.


Cover Story in Chemistry & Biology, from the group of Prof. William Scott (UC Santa Cruz) in collaboration with Prof. Darrin York (UMN) "Solvent Structure and Ribozyme Catalysis"; Vol 15, 332-342, 21 April 2008 (Link)

An area of intense experimental and theoretical research effort has been concentrated on elucidating how RNA molecules are able to catalyze complex biochemical reactions. A detailed understanding of the underlying mechanisms of these RNA enzymes provides insight into the inner workings of more complex cellular catalytic machinery such as the ribosome. Ultimately, these insights may aid the rational design of new medical therapies that target viral, neurological and genetic disease, as well as the development of new bio/nanotechnology.

Recently, the research group of Prof. Darrin York, including research associate Dr. Tai-Sung Lee, MSI research scholar Dr. Carlos Silva-Lopez and graduate student George Giambasu of the Department of Chemistry, in collaboration with Prof. Bill Scott of the Department of Chemistry, UCSC, have mapped out a plausible mechanism for the role of divalent metal ions in hammerhead ribozyme catalysis from molecular dynamics simulations (Fig. 1). Complementary work, done in collaboration with Prof. Jiali Gao of the Department of Chemistry and Dr. Kwangho Nam of the Department of Chemistry and Chemical Biology at Harvard University, on the hairpin ribozyme, suggest the electrostatic environment of the hairpin ribozyme accounts for the vast majority of its catalytic proficiency without recruitment of divalent metal ions involved in the chemical steps of the reaction (Fig. 2). Together, these studies provide two-fold insight into how molecules of RNA are able to catalyze biochemical reactions with and without chemical participation by divalent metal ions in the active site. The results of these two studies are currently in press in the Journal of the American Chemical Society.

One metal mechanism in hammerhead ribozyme derived from simulations of the reactant, early and late transition states.

Two-dimensional free energy profile for hairpin ribozyme calculated with a new AM1/d-PhoT model for phosphoryl transfer.

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