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Download fileEffect of Ring Size on Conformations of Aromatic Amine−DNA Adducts: The Aniline−C8 Guanine Adduct Resides in the B-DNA Major Groove
journal contribution
posted on 1998-04-03, 00:00 authored by Robert Shapiro, Stephen Ellis, Brian E. Hingerty, Suse BroydeWhile the one-ring amine aniline (AN) has only slight genetic
activity, the polycyclic aromatic
amines 2-aminofluorene (AF) and 1-aminopyrene (AP) are significant
mutagens and carcinogens. Moreover, the bulkier AP is more mutagenic per adduct than AF
in the tetracycline-resistance gene of plasmid pBR322 [Melchior et al. (1994)
Carcinogenesis 15, 889]. To
elucidate
possible conformational origins of the differing mutagenic effects of
these three adducts, which
may stem from their differing ring sizes, we have examined their
conformations in two
mutation-susceptible sequences from the above gene: TTGAG*GCCG
(sequence I) and
GAATG*GTGC (sequence II), where G* = C8-modified guanine. No
experimental high-resolution NMR data are yet available for the aniline adduct in a DNA
duplex. Minimized
potential energy calculations were carried out, using the molecular
mechanics program
DUPLEX to explore the conformation space of these adducts. In the
case of AN, a relatively
unperturbed B-DNA helix with the amine in the major groove was strongly
favored in both
sequences. In the case of AF- and AP-modified DNA, however,
several differing conformations
were competitive in energy. They included major groove structures,
as well as conformations
with syn-modified guanine and the polycyclic amine in the
minor groove, or the amine rings
intercalated into the helix with displacement of the modified guanine,
in overall harmony with
high-resolution NMR solution structures. Thus, aniline distorts
DNA structure to a lesser
extent than larger aromatic amine ring systems, since a number of
different conformations
are energetically feasible and have been observed for the larger
systems. This result may be
relevant to their enhanced mutagenicity and their repair propensity, in
contrast to aniline's
low mutagenic effect.
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Keywords
ring sizesconformation spaceguaninehelixTTGAGsequencemutagenic effectNMR datamechanics program DUPLEXgenerepair propensitygroove structuresamine ring systemsmutagenic effectsAdductGAATGbulkier APNMR solution structuresaniline adductamine rings intercalatedplasmid pBR 322Ring SizeDNA duplexDNA structureAFpolycyclic amineIIenergy calculations