Photoinduced DNA Lesions in Dormant Bacteria: The Peculiar Route Leading to Spore Photoproducts Characterized by Multiscale Molecular Dynamics

Some bacterial species enter a dormant state in the form of spores to resist to unfavorable external conditions. Spores are resistant to a wide series of stress agents, including UV radiation, and can last for tens to hundreds of years. Due to the suspension of biological functions, such as DNA repair, they accumulate DNA damage upon exposure to UV radiation. Differently from active organisms, the most common DNA photoproducts in spores are not cyclobutane pyrimidine dimers, but rather the so‐called spore photoproducts. This noncanonical photochemistry results from the dry state of DNA and its binding to small, acid‐soluble proteins that drastically modify the structure and photoreactivity of the nucleic acid. Herein, multiscale molecular dynamics simulations, including extended classical molecular dynamics and quantum mechanics/molecular mechanics based dynamics, are used to elucidate the coupling of electronic and structural factors that lead to this photochemical outcome. In particular, the well‐described impact of the peculiar DNA environment found in spores on the favored formation of the spore photoproduct, given the small free energy barrier found for this path, is rationalized. Meanwhile, the specific organization of spore DNA precludes the photochemical path that leads to cyclobutane pyrimidine dimer formation. Lying low: By using multiscale molecular modeling and simulation, the molecular mechanism that leads to the exclusive formation of spore photoproducts in dormant bacteria is rationalized. In particular, the peculiar condensation of DNA around the small, acid‐soluble protein significatively decreases the free energy barrier of the rate‐determining step, while also providing a less favorable environment for cyclobutane pyrimidine dimer formation.