Exposure of melanin to oxidative conditions has been found to generate dioxetanes that have the potential to induce DNA damage through chemical excitation and triplet sensitization. In particular, peroxynitrite is produced in such conditions, which interacts with melanin giving rise to decomposition products such as 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Subsequent reactivity between DHICA and peroxynitrite within the cell nucleus produces dioxetane derivatives, which then decompose, generating triplet excited states. These triplet states transfer energy to nucleobases, ultimately leading to pyrimidine dimerization in the DNA[1]. Other biomolecules with a similar molecular structure as DHICA and similar oxidation properties are expected to produce also dioxetanes and this type of damage under oxidative conditions. This is the case of serotonin, melatonin or tryptophan, with and indole skeleton.
Understanding the binding and unbinding interaction of the mentioned biomolecules and their dioxetanes with DNA is crucial in elucidating their relevance in the context of DNA damage. In this study, advanced sampling techniques employing the GAMBES[2] and OPES flooding[3,4] methods were utilized to compute the residence times in DNA and to characterize the binding/unbinding properties. The results obtained reveal that the release occurs on time scales of the order of µs, and the simulations have elucidated various unbinding mechanisms.