The long term objectives of the research described in this proposal are to understand the structure and function of biological macromolecules at the molecular level. The proposal describes a theoretical approach to the understanding of the conformation and dynamics of DNA. The focus is on electrostatic interactions and, in particular, on the contribution of solvation and ionic strength effects in screening pairwise electrostatic interactions and in stabilizing and destabilizing different DNA conformations as well as ligand-DNA interactions.
The specific aims i nclude: i) The development of methods to obtain total electrostatic energies from a complete Poisson-Boltzmann treatment of DNA conformation and ligand-DNA interactions. ii) The incorporation of the methods and results of a Poisson-Boltzmann treatment of solvent into molecular mechanics calculations and the application of these simulations to different phenomena. iii) The calculation of electrostatic potentials and ion distributions around different forms of DNA. iv) Calculating electrostatic contributions to conformational changes in DNA. v) Calculating electrostatic contributions to ligand-DNA binding energies. vi) Carrying out Monte-Carlo simulations of the ion atmosphere and of water structure around DNA. The basic approach is to use a model which combines a detailed atomic-level description of the DNA with a continuum treatment of the solvent. Electrical potentials are obtained by solving the non-linear Poisson Boltzmann equation, accounting for the charge distribution of the DNA, for the different polarizabilities of the macromolecule and solvent and for the effects of the ion atmosphere. The Poisson-Boltzmann equation is solved numerically using a finite difference approach applied previously to proteins. The health relatedness of the research is in the potential it offers in understanding DNA structure and function, and more specifically, in the insights and methodology it will provide for rational drug design.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041371-03
Application #
3299534
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Petrey, D; Honig, B (2000) Free energy determinants of tertiary structure and the evaluation of protein models. Protein Sci 9:2181-91
Norel, R; Petrey, D; Wolfson, H J et al. (1999) Examination of shape complementarity in docking of unbound proteins. Proteins 36:307-17
Abramovitz, D L; Friedman, R A; Pyle, A M (1996) Catalytic role of 2'-hydroxyl groups within a group II intron active site. Science 271:1410-3
Misra, V K; Honig, B (1996) The electrostatic contribution to the B to Z transition of DNA. Biochemistry 35:1115-24
Collini, M; Chirico, G; Baldini, G et al. (1995) Conformation of short DNA fragments by modulated fluorescence polarization anisotropy. Biopolymers 36:211-25
Friedman, R A; Honig, B (1995) A free energy analysis of nucleic acid base stacking in aqueous solution. Biophys J 69:1528-35
Misra, V K; Honig, B (1995) On the magnitude of the electrostatic contribution to ligand-DNA interactions. Proc Natl Acad Sci U S A 92:4691-5
Honig, B; Nicholls, A (1995) Classical electrostatics in biology and chemistry. Science 268:1144-9
Sharp, K A; Friedman, R A; Misra, V et al. (1995) Salt effects on polyelectrolyte-ligand binding: comparison of Poisson-Boltzmann, and limiting law/counterion binding models. Biopolymers 36:245-62
Misra, V K; Hecht, J L; Sharp, K A et al. (1994) Salt effects on protein-DNA interactions. The lambda cI repressor and EcoRI endonuclease. J Mol Biol 238:264-80

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