Date of Graduation


Document Type


Degree Type



School of Medicine


Microbiology, Immunology, and Cell Biology

Committee Chair

Peter M. Gannett.


Thermal denaturation, circular dichroism, and NMR have been used extensively in conformational studies of oligonucleotides. Molecular modeling has become a powerful, if not essential, complement to these experimental techniques. To study the effects of C8-arylated purine adducts caused by carcinogenic aryl hydrazines we combined the two approaches. Two oligonucleotides were prepared, an unmodified oligonucleotide d(5'CGCGCGCGCG 3') and a C8-phenylguanine modified oligonucleotide d( 5'CGCGCG*CGCG3') (G* = 8-phenylguanine). These oligonucleotides were compared using thermal denaturation, circular dichroism, and NMR. The phenyl modification destabilizes the B DNA form and stabilizes the Z DNA form such that the B:Z ratio is near one under physiological conditions.;Modeling studies were conducted on the modified sequence with G* = guanine, G* = 8-phenylguanine, G* = 8-tolylguanine, and G* = 8-hydroxymethylphenylguanine in the B and ZDNA conformations. We performed quantum mechanical calculations at the B3LYP level with the standard 6-31 G* basis set using Gaussian98, and molecular dynamics simulations and free energy calculations using the suite of programs contained in Amber 6 and 7 with the Cornell 95 force field. New parameters for the modified guanines (G*) have been developed for the Cornell force field. Structural and thermodynamic properties of the DNA molecules are described from the analysis of the trajectories.;The phenyl and tolyl-modified DNA's favored the Z form and the B conformation was preferred by the unmodified and hydroxymethylphenyl-modified oligonucleotides. In those cases where experimental data was available, it was in agreement with the theoretical data. The phenyl-modified models were useful in supporting and providing explanation for the experimental results. In light of recent studies, which show a role for Z DNA in gene expression and cell transformation, Z DNA stabilization by C8-arylguanine formation from aryl hydrazines may be relevant to their role in carcinogenesis.