COMP 25 |
| Ribonuclease H (RNase H) is a sequence-nonspecific endonuclease, which catalyzes the hydrolysis of phosphodiester linkages of the RNA strand in presence of Mg or Mn cations, and degrades RNA·DNA hybrids. RNase H 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 RNase H, we investigate its catalytic mechanism combining classical molecular dynamics (MD) and first principles quantum mechanics/molecular mechanics (QM/MM) dynamics. First, the wild type enzyme and relevant mutants are modeled by MD within different buffer conditions in order to study the still unclear role of second metal shell residues in tuning the catalysis. Then, the bimetal-aided nucleotidyl transfer reaction is investigated by QM/MM calculations and discussed on the basis of experimental evidences. The results evidence the highly associative enzymatic mechanism for phosphoryl transfer, which involves the formation of a meta-stable phosphorane intermediate stabilized by the two Mg metal ions. Importantly, this information might eventually provide a blueprint for the design of specific inhibitors. |
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Protein-Nucleic Acid Interactions: Experimental and Modeling Analysis
8:30 AM-12:15 PM, Sunday, August 19, 2007 BCEC -- 156B, Oral
Division of Computers in Chemistry |