10.1021/acs.jcim.8b00238.s001
Ryan W. Kung
Ryan
W. Kung
Purshotam Sharma
Purshotam
Sharma
Stacey D. Wetmore
Stacey D.
Wetmore
Effect of Size and Shape of Nitrogen-Containing Aromatics
on Conformational Preferences of DNA Containing Damaged Guanine
American Chemical Society
2018
AMBER
DNA Containing Damaged Guanine
dG adducted DNA
MD
3LYP
model DNA lesions
DFT
C 8
NCA moiety shape
2018-06-20 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Effect_of_Size_and_Shape_of_Nitrogen-Containing_Aromatics_on_Conformational_Preferences_of_DNA_Containing_Damaged_Guanine/6771299
The
present work investigates the effects of the size and shape
of the nitrogen-containing aromatic (NCA) skeleton on the structure
of DNA damaged through adduct formation at C<sup>8</sup> of 2′-deoxyguanosine
(dG), a common DNA lesion associated with chemical carcinogenesis.
Specifically, density functional theory (DFT) calculations (B3LYP-D3)
and molecular dynamics (MD) simulations (AMBER) are performed on seven
model adducts with systematic expansion of the NCA moiety. DFT calculations
reveal that the NCA moiety shape affects the structure at the nucleobase–carcinogen
linkage. Approximately 4.5 μs of MD simulations on damaged oligonucleotides
adopting three established conformational themes (namely, B, W, and
S) illustrate that the structure and lesion-site stabilization strongly
depend on the NCA moiety shape and size, which provides insight into
the repair propensity of C<sup>8</sup>-dG adducted DNA. Our results
add bulky moiety shape to the growing list of previously established
effects on the conformational and repair outcomes of damaged DNA (i.e.,
size, ionization state, substitution, linker type, and DNA sequence).
Furthermore, this work illustrates the utility of a systematic set
of model DNA lesions for understanding the structure–activity
relationship for DNA damaged by carcinogens of different sizes and
shapes, which should be used in future studies of the cellular processing
of damaged DNA.