1 research outputs found
Structure, Dynamics, and Interactions of a C4′-Oxidized Abasic Site in DNA: A Concomitant Strand Scission Reverses Affinities
Apurinic/apyrimidinic
(AP) sites constitute the most frequent form
of DNA damage. They have proven to produce oxidative interstrand cross-links,
but the structural mechanism of cross-link formation within a DNA
duplex is poorly understood. In this work, we study three AP-containing
dÂ[GCÂGÂCÂGÂCÂXÂCÂGÂCÂGÂCÂG]·dÂ[CÂGÂCÂGÂCÂGÂKÂGÂCÂGÂCÂGC]
duplexes, where X = C, A, or
G and K denotes an α,β-unsaturated ketoaldehyde derived
from elimination of a C4′-oxidized AP site featuring a 3′
single-strand break. We use explicit solvent molecular dynamics simulations,
complemented by quantum chemical density functional theory calculations
on isolated X:K pairs. When X = C, the K moiety in the duplex flips
around its glycosidic bond to form a stable C:K pair in a near-optimal
geometry with two hydrogen bonds. The X = A duplex shows no stable
interaction between K and A, which contrasts with AP sites lacking
a strand scission that present a preferential affinity for adenine.
Only one, transient G:K hydrogen bond is formed in the X = G duplex,
although the isolated G:K pair is the
most stable one. In the duplex, the stable C:K pair induces unwinding
and sharp bending into the major groove at the lesion site, while
the internal structure of the flanking DNA remains unperturbed. Our
simulations also unravel transient hydrogen bonding between K and
the cytosine 5′ to the orphan base X = A. Taken
together, our results provide a mechanistic explanation for the experimentally
proven high affinity of C:K sites in forming cross-links in DNA duplexes
and support experimental hints that interstrand cross-links can be
formed with a strand offset