Mechanism of the <i>cis</i>-[Pt(1<i>R</i>,2<i>R</i>‑DACH)(H₂O)₂]²⁺ Intrastrand Binding to the Double-Stranded (pGpG)·(CpC) Dinucleotide in Aqueous Solution: A Computational DFT Study

A mechanism of the intrastrand 1,2-cross-link formation between the double-stranded pGpG·CpC dinucleotide (ds­(pGpG)) and fully aquated oxaliplatin <i>cis</i>-[Pt­(DACH)­(H₂O)₂]²⁺ (DACH = cyclohexane-1<i>R</i>,2<i>R</i>-diamine) is presented. All structures of the reaction pathways including the transition states (TSs) were fully optimized in water solvent using DFT methodology with dispersion corrections. Both 5′ → 3′ and 3′ → 5′ binding directions were considered. In the first step there is a slight kinetic preference for 5′-guanine (5′G) monoadduct formation with an activation Gibbs free energy of 18.7 kcal/mol since the N7 center of the 5′G base is fully exposed to the solvent. On the other hand, the N7 atom of 3′-guanine (3′G) is sterically shielded by 5′G. The lowest energy path for formation of the 3′G monoadduct with an activation barrier of 19.3 kcal/mol is connected with a disruption of the ‘DNA-like’ structure of ds­(pGpG). Monoadduct formation is the rate-determining process. The second step, chelate formation, is kinetically preferred in the 3′ → 5′ direction. The whole process of the platination is exergonic by up to −18.8 kcal/mol. Structural changes of ds­(pGpG), charge transfer effects, and the influence of platination on the G·C base pair interaction strengths are also discussed in detail