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

Emmanuelle Bignon (1, 2) , Tomáš Dršata (3) , Christophe Morell (2) , Filip Lankaš (4, 3) , Elise Dumont (1)

1 LC - Laboratoire de Chimie - UMR5182
2 Chemometrics and theoretical chemistry. - Chimiométrie et chimie théorique
3 IOCB / CAS - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
4 Laboratory of Informatics and Chemistry

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.

Mots clés: dna; palliative care; solvents; purines; cross-linking; dna replication

Domaines: Radiochimie; Chimie analytique; Chimie théorique et/ou physique; Biochimie [q-bio.BM]

Emmanuelle Bignon, Tomáš Dršata, Christophe Morell, Filip Lankaš, Elise Dumont. Interstrand cross-linking implies contrasting structural consequences for DNA: insights from molecular dynamics. Nucleic Acids Research, 2017, 45 (4), pp.2188-2195. ⟨10.1093/nar/gkw1253⟩. ⟨hal-01449663⟩