Abstract

This project aims to apply classical and quantum chemical techniques to structural questions related to HIV pathogenesis, in particular those involving HIV-1 protease and the HIV-1 reverse transcriptase. We are currently performing quantum mechanical calculations on models of the active site in an effort to define the transition state of the protease. Knowing how the hydrolysis takes place should motivate the design of blocking agents. We have built small models of the active site which identified the key intermediates in the reaction cycle. We plan to expand the model to include more of the environment of the key residues. We are also working with the Kunkel/ Bebenek lab to model the HIV-RT/DNA interaction in the """"""""thumb"""""""" domain in order to provide a structural basis for discussing the results of their mutagenesis studies relating to polymerase processivity and fidelity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES090601-01
Application #
5202292
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
National Institute of Environmental Health Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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
Jiao, Dian; Golubkov, Pavel A; Darden, Thomas A et al. (2008) Calculation of protein-ligand binding free energy by using a polarizable potential. Proc Natl Acad Sci U S A 105:6290-5
Cisneros, G Andres; Elking, Dennis; Piquemal, Jean-Philip et al. (2007) Numerical fitting of molecular properties to Hermite Gaussians. J Phys Chem A 111:12049-56
Gresh, Nohad; Cisneros, G Andres; Darden, Thomas A et al. (2007) Anisotropic, Polarizable Molecular Mechanics Studies of Inter- and Intramolecular Interactions and Ligand-Macromolecule Complexes. A Bottom-Up Strategy. J Chem Theory Comput 3:1960-1986
Elking, Dennis; Darden, Tom; Woods, Robert J (2007) Gaussian induced dipole polarization model. J Comput Chem 28:1261-74
Babin, Volodymyr; Baucom, Jason; Darden, Thomas A et al. (2006) Molecular dynamics simulations of DNA with polarizable force fields: convergence of an ideal B-DNA structure to the crystallographic structure. J Phys Chem B Condens Matter Mater Surf Interfaces Biophys 110:11571-81
Hamburgh, Monica E; Curr, Kenneth A; Monaghan, Melissa et al. (2006) Structural determinants of slippage-mediated mutations by human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 281:7421-8
Cisneros, G Andres; Piquemal, Jean-Philip; Darden, Thomas A (2006) Generalization of the Gaussian electrostatic model: extension to arbitrary angular momentum, distributed multipoles, and speedup with reciprocal space methods. J Chem Phys 125:184101
Fisher, Timothy S; Darden, Tom; Prasad, Vinayaka R (2003) Mutations proximal to the minor groove-binding track of human immunodeficiency virus type 1 reverse transcriptase differentially affect utilization of RNA versus DNA as template. J Virol 77:5837-45
Fisher, Timothy S; Darden, Tom; Prasad, Vinayaka R (2003) Substitutions at Phe61 in the beta3-beta4 hairpin of HIV-1 reverse transcriptase reveal a role for the Fingers subdomain in strand displacement DNA synthesis. J Mol Biol 325:443-59