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.
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