The Impact of rAdo and OXOdGuo on the Electronic Properties of Clustered DNA Lesions: A Theoretical Approach

Ribonucleotides and 7,8-dihydro-8-oxo-2′-deoxyguanosine (OG) are frequently incorporated into genomic DNA as non-canonical moieties; their local co-occurrence can lead to the formation of clustered DNA lesions (CDLs) which may not be susceptible to repair. Their estimated co-occurrence within two helical turns may reach ~650 incidents per diploid genome and can increase in pathological states. The results presented in this article show the influence of riboadenosine (rAdo) on the structural and electronic properties of double-stranded (ds) DNA containing OG. For this purpose, four ds-pentamers representing different mutual rAdo and OG topology, i.e., d[A1G2rA3OG4A5]*d[T5C4T3C2T1] (GrAOG-DNA), d[A1OG2rA3G4A5]*d[T5C4T3C2T1] (OGrAG-DNA), d[A1G2rA3G4A5]*d[T5C4OG3C2T1] (rAOG-DNA) and d[A1G2rA3OG4A5]*d[T5C4T3A2T1] (OGA-DNA), have been selected and theoretically investigated at a M06-2X/6-31++G**//M06-2X/D95**:M06-2X/sto-3G level of theory in aqueous solution. The study examines their spatial geometry, stacking interactions, charge and spin distributions, Fukui functions, global reactivity descriptors, and vertical/adiabatic ionisation potentials and electron affinities. The above parameters of ds-oligonucleotides were found to be strongly dependent on topology. rAOG-DNA was the most resistant to charge-induced structural rearrangement, whereas OGA-DNA was the most responsive and exhibited the highest electron-accepting tendency: its adiabatic electron affinity was 4.07 eV, compared to 2.01 eV for rAOG-DNA. Also, rAOG-DNA and OGA-DNA demonstrated proton transfer accompanying relaxation of the radical cation state together with charge–spin separation. These findings indicate that rAdo can reshape the electronic landscape of OG-containing CDLs and may influence DNA damage recognition and repair. Such topology-dependent effects may play important parts in genome instability and treatment-associated DNA damage responses.