Theoretical analyses on a flipping mechanism of UV-induced DNA damage

As for UV-induced DNA damage, which may induce skin cancer in animals and growth inhibition in plants, there are two types of photoproducts, namely cis-sin cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts. When they are to be repaired, base-flipping occurs, and they bind to enzymes. However, this process remains relatively unknown at a molecular level. We analyze conformation and interaction energy changes upon base-flipping using classical molecular dynamics (CMD) simulations and ab initio electronic structure calculations. CMD simulations starting with a CPD in the flipped-in and flipped-out states showed that both states were unchanged for 500 ns, indicating the flipped-in and flipped-out processes do not occur spontaneously (without any help of the enzyme) after photo-damage. To deeply understand the reasons, we investigated interaction energy changes among bases upon structure changes during the flipped-in and flipped-out processes using Parallel Cascade Selection-MD (PaCS-MD) simulations at 400 K, followed by a fragment molecular orbital (FMO) method. The total inter-fragment interaction energy (IFIE) between CPD and other bases at the flipped-in state is estimated to be -60.08 kcal/mol. In particular, four bases strongly interact with CPD with interaction energies being -10.96, -13.70, -21.52, and -14.46 kcal/mol each. On the other hand, the total IFIE at the obtained flipped-out state increased to -10.40 kcal/mol by partly losing hydrogen bonds and π-π stacking interactions, respectively. These results clearly indicate that the base-flipping process of DNA lesions occurs with the help of external forces like interactions with appropriate enzymes such as photolyases.