bi700858s_si_003.pdf (550.63 kB)
Spectroscopic and Theoretical Insights into Sequence Effects of Aminofluorene-Induced Conformational Heterogeneity and Nucleotide Excision Repair†,∇
journal contribution
posted on 2007-10-09, 00:00 authored by Srinivasa Rao Meneni, Steven M. Shell, Lan Gao, Petr Jurecka, Wang Lee, Jiri Sponer, Yue Zou, M. Paul Chiarelli, Bongsup P. ChoA 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*N- 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.
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dG adductUvrABC proteinsheterogeneityduplexeS conformationseriesvan der Waals energy force field calculationsbase pairscarcinogenbase sequencesDNA adductsUVTheoretical Insightsmillisecond rangeB conformerspurine basesSimulation analysisCGrepair susceptibilitymannerFAFB conformationAG19 F NMR spectroscopyinteraction energiesSequence Effectssolvation effectscorrelationquantum mechanics calculations
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