Spectroscopic and theoretical insights into sequence effects of aminofluorene-induced conformational heterogeneity and nucleotide excision repair

Authors

Srinivasa Rao Meneni, University of Rhode Island
Steven M. Shell, Quillen-Dishner College of Medicine
Lan Gao, Loyola University of Chicago
Petr Jurecka, Institute of Biophysics of the Academy of Sciences of the Czech Republic
Wang Lee, University of Rhode Island
Jiri Sponer, Institute of Biophysics of the Academy of Sciences of the Czech Republic
Yue Zou, Quillen-Dishner College of Medicine
M. Paul Chiarelli, Loyola University of Chicago
Bongsup P. Cho, University of Rhode Island

Document Type

Article

Date of Original Version

10-9-2007

Abstract

A systematic spectroscopic and computational study was conducted in order to probe the influence of base sequences on stacked (S) versus B-type (B) conformational heterogeneity induced by the major dG adduct derived from the model carcinogen 7-fluoro-2-aminofluorene (FAF). We prepared and characterized eight 12-mer DNA duplexes (-AG*N- series, d[CTTCTAG*NCCTC]; -CG*W- series, d[CTTCTCG*NCCTC]), in which the central guanines (G*) were site-specifically modified with FAF with varying flanking bases (N = G, A, C, T). S/B heterogeneity was examined by CD, UV, and dynamic 19F NMR spectroscopy. All the modified duplexes studied followed a typical dynamic exchange between the S and B conformers in a sequence dependent manner. Specifically, purine bases at the 3′-flanking site promoted the S conformation (G > A > C > T). Simulation analysis showed that the S/B energy barriers were in the 14-16 kcal/mol range. The correlation times (τ = 1/κ) were found to be in the millisecond range at 20°C. The van der Waals energy force field calculations indicated the importance of the stacking interaction between the carcinogen and neighboring base pairs. Quantum mechanics calculations showed the existence of correlations between the total interaction energies (including electrostatic and solvation effects) and the S/B population ratios. The S/B equilibrium seems to modulate the efficiency of Escherichia coli UvrABC-based nucleotide excision repair in a conformation-specific manner: i.e., greater repair susceptibility for the S over B conformation and for the -AG*N- over the -CG*N- series. The results indicate a novel structure-function relationship, which provides insights into how bulky DNA adducts are accommodated by UvrABC proteins. © 2007 American Chemical Society.

Publication Title, e.g., Journal

Biochemistry

Volume

46

Issue

40

Citation/Publisher Attribution

Meneni, Srinivasa R., Steven M. Shell, Lan Gao, Petr Jurecka, Wang Lee, Jiri Sponer, Yue Zou, M. P. Chiarelli, and Bongsup P. Cho. "Spectroscopic and theoretical insights into sequence effects of aminofluorene-induced conformational heterogeneity and nucleotide excision repair." Biochemistry 46, 40 (2007): 11263-11278. doi: 10.1021/bi700858s.