Interstrand cross-linking implies contrasting structural consequences for DNA: insights from molecular dynamics

Abstract

Oxidatively-generated interstrand cross-links rank among the most deleterious DNA lesions. They originate from abasic sites, whose aldehyde group can form a covalent adduct after condensation with the exocyclic amino group of purines, sometimes with remarkably high yields. We use explicit solvent molecular dynamics simulations to unravel the structures and mechanical properties of two DNA sequences containing an interstrand cross-link. Our simulations palliate the absence of experimental structural and stiffness information for such DNA lesions and provide an unprecedented insight into the DNA embedding of lesions that represent a major challenge for DNA replication, transcription and gene regulation by preventing strand separation. Our results based on quantum chemical calculations also suggest that the embedding of the ICL within the duplex can tune the reaction profile, and hence can be responsible for the high difference in yields of formation.

Recognition of a tandem lesion by DNA bacterial formamidopyrimidine glycosylases explored combining molecular dynamics and machine learning

“…The parameters for 8-oxoG and Ap site have been generated with a standard antechamber procedure embedded in Amber 18 [63] , as described in previous references [68] , [69] , [70] and in agreement to the literature. The abasic site was modeled as an alpha anomer, and the Q166C mutation in the crystal was conserved to start from a structure as close to experimental data as possible.…”

Recognition of a Tandem Lesion by DNA Glycosylases Explored Combining Molecular Dynamics and Machine Learning

“…The parameters for 8-oxoG and Ap site have been generated with a standard antechamber procedure embedded in Amber 18 47 , as described in previous references [51][52][53] and in agreement to the literature. Four 10,000 steps minimization runs were carried out on the initial MutM:DNA complex, imposing restraints on the amino and nucleic acids, that were gradually decreased from 20 to 0 kcal/mol/Å 2 along the four runs.…”

Nucleosomal embedding reshapes the dynamics of abasic sites

“…Molecular dynamics has become a dominant method to shed insights on: structural 21 and mechanical properties 22 , reactivity and repair of AP sites 23 – 25 , and effects of clustered AP sites 26 , 27 . A few all-atom molecular dynamics simulations have been performed on NCPs, undamaged 28 – 30 , stacked 31 , with double-strand breaks 32 , or harboring acetylated histone tails 33 .…”