Quantum chemistry study on the feasibility of triplet-triplet energy transfer in the dark photosensitization of DNA.

Cyclobutane pyrimidine dimers (CPDs) are classically formed in DNA upon ultraviolet (UV) irradiation; however, recent evidences demonstrate that CPDs can also arise in the dark. This mechanism involves the formation of dioxetanes from reactions between peroxynitrite and indole-like biomolecules (5,6-dihydroxy-1H-indole-2-carboxylic acid (DHICA), tryptophan, melatonin, and serotonin). Subsequent dioxetane decomposition generates triplet-excited states capable of transferring energy to DNA thymine bases via triplet-triplet energy transfer (TTET), ultimately leading to CPD formation. In this work, we computationally determine and compare the triplet excitation energies of these indole derivatives and DNA nucleobases in the gas phase and in aqueous solution using density functional theory to assess the relative trends for TTET. Tryptophan is identified as the most efficient potential dark photosensitizer, followed by DHICA, melatonin and serotonin. To rationalize the experimental observations of CPD formation in thymine within DNA, we integrate our computed properties with previous computational and experimental data to propose a mechanistic framework for TTET in DNA. In this proposed mechanism, dioxetanes are assumed to associate with DNA before undergoing chemiexcitation, leading to the formation of triplet-excited photosensitizers capable of TTET. This proposal provides a coherent interpretation of the experimental evidence of DNA photodamage in the dark induced by DHICA, tryptophan, melatonin and serotonin.