The long range goal of this project is to develop and apply theoretical methods which will allow the accurate simulation of the structures and free energies of nucleic acids and their non- covalent and covalent adducts with other molecules. A major objective of the next period of grant support is the extension and application of free energy perturbation, molecular dynamics, quantum mechanical and distance geometry methodologies to a wide variety of systems involving DNA and RNA. Studies on DNA-anticancer drugs may lead to new insights into drug design. Studies of carcinogenic DNA adducts could give insight into what makes them carcinogenic. The process of recognition of sites of DNA by small molecules should allow the design of molecules which interact with specific sites on DNA. These methodologies should enable a more accurate representation of the conformational equilibria and free energies for the basis of biophysical processes of nucleic acids (e.g. double helix formation, bulge formation, A leads to B leads to Z transition energetics, sequence dependent DNA and RNA dynamics and equilibria). They also should allow quantitative calculations and predictions of relative free energies of associations of small molecules to DNA and RNA. They will allow a more accurate representation of structures and energies of DNA-covalent adduct formation. The calculation will give new and quantitative insight into the nature of DNA recognition by proteins. Important spinoffs of these studies may be new insights into the biological consequence of nucleic acid interactions with other molecules.
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