Efficiency of bimetal-aided phosphodiester bond cleavage in nucleotidyl transfer reactions

COMP 51

Matteo Dal Peraro, matteodp@cmm.upenn.edu1, Marco De Vivo, mdevivo@cmm.upenn.edu1, and Michael L. Klein, klein@seas.upenn.edu2. (1) Center for Molecular Modeling, Chemistry Department, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, (2) Department of Chemistry, University of Pennsylvania, 231 S. 34th St., Philadelphia, PA 19104-6323
Ribonuclease H (RNase H) belongs to the nucleotidyl-transferase superfamily and catalyzes, in presence of Mg2+ or Mn2+ ions, the hydrolysis of phosphodiester linkages of the RNA strand, degrading RNA·DNA hybrids. It is involved in a number of biochemical processes such as replication initiation and DNA topology restore, being also a promising target for anti-HIV drug design. Based on recent crystallographic structures of Bacillus halodurans (Bh) RNase H, we investigate possible reaction mechanisms applying a hierarchical computational approach, which combine classical force field-based and advanced quantum mechanical methods (Car-Parrinello QM/MM calculations). We offer first-principles-based insights of mechanistic details of the enzymatic bimetal-aided nucleotidyl transfer reaction and possible interpretations of experimental evidences, proposing reasons governing either catalytic or inhibitory effects of different divalent metal-ions. Importantly, these results might inspire the design of specific inhibitors based on the enzymatic reaction transition state.
 

General Oral: Quantum Chemistry
1:00 PM-5:00 PM, Sunday, 10 September 2006 Moscone Center -- Room 208/210, Oral

Division of Computers in Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006