B. Mao et al., Solution structure of the (+)-cis-anti-benzo[a]pyrene-dA ([BP]dA) adduct opposite dT in a DNA duplex, BIOCHEM, 38(33), 1999, pp. 10831-10842
Minor adducts, derived from the covalent binding of anti-benzo [a]pyrene-7,
8 -dihydroxy-9,-10-epoxide to cellular DNA, may play an important role in g
enerating mutations and initiating cancer. We have applied a combined NMR-c
omputational approach including intensity based refinement to determine the
solution structure of the minor (+)-cis-anti-[BP]dA adduct positioned oppo
site dT in the d(C1-T2-C3-T4-C5-[BP]A6-C7-T8-T9-C10-C11).(d(G12-G13-A14-A15
-G16-T17-G18A19-G20-A21-G22) 11-mer duplex. The BP ring system is intercala
ted toward the 5'-side of the [BP]dA6 lesion site without disrupting the fl
anking Watson-Crick dC5.dG18 and [BP]dA6.dT17 base pairs. This structure of
the (+)-cis-anti-[BP]dA.dT 11-mer duplex, containing a bay region benzo[a]
pyrenyl [BP]dA adduct, is compared with the corresponding structure of the
(+)-trans-anti-[BPh]dA.dT 11-mer duplex (Cosman et al., Biochemistry 32, 12
488-12497, 1993), which contains a fjord region benzo[c]phenanthrenyl [BPh]
dA adduct with the same R stereochemistry at the linkage site. The carcinog
en intercalates toward the 5'-direction of the modified strand in both dupl
exes (the adduct is embedded within the same sequence context) with the buc
kling of the Watson-Crick [BP]dA6.dT17 base pair more pronounced in the (+)
-cis-anti-[BP]dA.dT 11-mer duplex compared to its Watson-Crick [BPh]dA.dT17
base pair in the (+)-trans-anti- [BPh]dA.dT 11-mer duplex. The available s
tructural studies of covalent polycyclic aromatic hydrocarbon (PAH) carcino
gen-DNA adducts point toward the emergence of a general theme where distinc
t alignments are adopted by PAH adducts covalently linked to the N-6 Of ade
nine when compared to the N-2 of guanine in DNA duplexes. The [BPh]dA and [
BP]dA N-6-adenine adducts intercalate their polycyclic aromatic rings into
the helix without disruption of their modified base pairs. This may reflect
the potential flexibility associated with the positioning of the covalent
tether and the benzylic ring of the carcinogen in the sterically spacious m
ajor groove. By contrast, such an intercalation without modified base pair
disruption option appears not to be available to [BP]dG N-2-guanine adducts
where the covalent tether and the benzylic ring are positioned in the more
sterically crowded minor groove. In the case of [BP]dG adducts, the benzop
yrenyl ring is either positioned in the minor groove without base pair disr
uption, or if intercalated into the helix, requires disruption of the modif
ied base pair and displacement of the bases out of the helix.