Probing Interstand CrossLinks Impact on DNA Structure by Classical Molecular Dynamics Simulations
Résumé
Interstrands cross-links are highly cytotoxic oxidatively-generated DNA damages. They result from abasic sites (Ap) reaction with a purine on the facing strand of the double-helix. The aldehyde group of the abasic site condenses with the exocyclic amino group of the purine, leading to a covalent adduct, bonding the two strands.
This type of lesions is very deleterious for cells since it avoids the strands separation during DNA replication, leading to apoptosis [1]. The feasability of such lesions has been prooved [2,3], with high yields (15-70%) reported for the formation of Ap-Adenine cross linking [4]. These observations suggest that B-helix is flexible enough to allow the two reactants to approach and react, despite the mechanical constraints that it could induce.
We investigated the structural impact of these interstrands cross-links in 21 base pair oligonucleotides, generating 100ns molecular dynamics simulations. Structural analysis on these conformationnal sampling allowed us to probe the effect of such lesions on the double-helix. This study showed strong structural rearrangements in the double-helix, presenting two stable conformations, both with π-stacking modifications of the surrounding nucleobases and C33 exclusion, the difference between the two relying on the T12 exclusion.
[1] Formation and Repair of Interstrand Cross- Links in DNA (Noll et al.), Chem. Rev. 106, 277-301 (2006).
[2] Scope and Mechanism of Interstrand Cross-Link Formation by the C4’-Oxidized Abasic Site (Sczepanski et al.), J. Am. Chem. Soc. 131, 11132-11139 (2009).
[3] Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion (Regulus et al.), Proc. Natl. Acad. Sci. U.S.A 104, 14032-14037 (2007).
[4] Interstrand DNA-DNA cross-link formation between adenine residues and abasic sites in duplex DNA (Price et al.), J. Am. Chem. Soc. 136, 3483-3490 (2014).