Transition State Studies for the HIV Protease and DNA Polymerase

Darden, Thomas A.

Abstract

of Work: The goal of this work is to produce an accurate all atom model of the HIV-1 Reverse Transcriptase (RT) complexed to DNA, and to use this model to help design and interpret studies of the effect of mutations in the protein and sequence modifications in the DNA on processivity and fidelity of HIV replication. The model may also be useful to other groups who are studying this complex.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES090601-04
• Application #: 6106799
• Study Section: Special Emphasis Panel (LSB)
• Support Year: 4
• Fiscal Year: 1998

Institution

• Name: National Institute of Environmental Health Sciences
• Country: United States

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