In this year we devoted extensive effort to the development of improved force fields that can interface seamlessly with quantum chemical methods, in particular Density Functional Theory, to study the reaction mechanism of the RNASE-H and polymerase active sites of the HIV-1 reverse transcriptase. Due to the high concentration of charged amino acid and nucleic acid residues, as well as the presence of metal ions, the treatment of short ranged and long ranged electrostatics is critical to achieving reliable results. We have performed mixed quantum chemical/ clasical simulations of the reaction mechanism of the human pol lambda DNA polymerase ternary complex and the epsilon exonuclease enzyme, which provides the main proofreading functionality for DNA replication in the common E. Coli bacteria. As well as being of fundamental importance in themselves, these systems, being much better characterized structurally (higher resolution) than the corresponding active sites in HIV-1 reverse transcriptase, provide important tests of the quality of our developed methods.
| Cisneros, G Andrés; Perera, Lalith; Schaaper, Roel M et al. (2009) Reaction mechanism of the epsilon subunit of E. coli DNA polymerase III: insights into active site metal coordination and catalytically significant residues. J Am Chem Soc 131:1550-6 |
| Li, Wenxue; Huang, Yan; Reid, Rollie et al. (2008) NMDA receptor activation by HIV-Tat protein is clade dependent. J Neurosci 28:12190-8 |
| Cisneros, G Andres; Perera, Lalith; Garcia-Diaz, Miguel et al. (2008) Catalytic mechanism of human DNA polymerase lambda with Mg(2+) and Mn(2+) from ab initio quantum mechanical/molecular mechanical studies. DNA Repair (Amst) 7:1824-34 |
