Abstract

New computational approaches to the simulation of nucleic acid interactions will be developed, including improved molecular mechanical force fields, new methods to calculate free energies and new methods to enhance conformational sampling. These new approaches will be applied to DNA and RNA the structures and the interactions of DNA and RNA with proteins and small molecule Iigands. The goal is to accurately reproduce experimental structures and free energies of binding in these systems when these are known. Applications include interactions of DNA with anticancer drug daunonycin and its analogs, minor groove topoisomerase I inhibitors which have anti-cancer activity, and polyamides which are among the most promising therapeutic approaches to target specific DNA sequences, as well as interactions of DNA with both binding proteins (the zinc finger Zif 268) and proteins that catalyze specific site cleavage of the DNA (Eco RV). Dr. Kollman will also study RNA-ligand interactions which are relevant in anti-viral and anti-AIDS chemotherapy, as well as elucidating the mechanism of catalysis of the ribosome, certainly the most important ribozyme yet discovered.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA025644-22
Application #
6370611
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Lees, Robert G
Project Start
1980-01-01
Project End
2003-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
22
Fiscal Year
2002
Total Cost
$290,419
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Wang, Junmei; Kang, Xinshan; Kuntz, Irwin D et al. (2005) Hierarchical database screenings for HIV-1 reverse transcriptase using a pharmacophore model, rigid docking, solvation docking, and MM-PB/SA. J Med Chem 48:2432-44
Tonelli, Marco; Ulyanov, Nikolai B; Billeci, Todd M et al. (2003) Dynamic NMR structures of [Rp]- and [Sp]-phosphorothioated DNA-RNA hybrids: is flexibility required for RNase H recognition? Biophys J 85:2525-38
Reyes, C M; Kollman, P A (2000) Structure and thermodynamics of RNA-protein binding: using molecular dynamics and free energy analyses to calculate the free energies of binding and conformational change. J Mol Biol 297:1145-58
Kollman, P A; Massova, I; Reyes, C et al. (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889-97
Reyes, C M; Kollman, P A (2000) Investigating the binding specificity of U1A-RNA by computational mutagenesis. J Mol Biol 295:6-Jan
Cheatham 3rd, T E; Cieplak, P; Kollman, P A (1999) A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. J Biomol Struct Dyn 16:845-62
Konerding, D E; Cheatham 3rd, T E; Kollman, P A et al. (1999) Restrained molecular dynamics of solvated duplex DNA using the particle mesh Ewald method. J Biomol NMR 13:119-31
Reyes, C M; Kollman, P A (1999) Molecular dynamics studies of U1A-RNA complexes. RNA 5:235-44
Srinivasan, J; Miller, J; Kollman, P A et al. (1998) Continuum solvent studies of the stability of RNA hairpin loops and helices. J Biomol Struct Dyn 16:671-82
Cheatham 3rd, T E; Srinivasan, J; Case, D A et al. (1998) Molecular dynamics and continuum solvent studies of the stability of polyG-polyC and polyA-polyT DNA duplexes in solution. J Biomol Struct Dyn 16:265-80

Showing the most recent 10 out of 52 publications