Challenges in computing electron-transfer energies of DNA repair using hybrid QM/MM models

The influence of the molecular environment on chemical activity is an important factor in biomolecular mechanisms. We studied the effects of ionic groups, that is, a protonated histidine side chain and deprotonated phosphates of DNA, on electron transfer in light-induced DNA repair. On the basis of the X-ray crystal structure, we prepared a hybrid QM/MM model of the macromolecular complex formed between the (6-4) photolyase enzyme and the DNA substrate containing the thymine-thymine (6-4) photoproduct. At the optimized geometries, we computed with the CASSCF and CASPT2 methods the excited states of the electron donor and electron acceptor complex, consisting of the reduced flavin and the (6-4) photoproduct. The donor-acceptor complex interacts with its environment comprised of the protein, the double-stranded DNA substrate with its counterions, and the solvating water molecules, which we modeled using the AMBER94 force field. The excited states of our interest include two locally excited (LE) states of the flavin chromophore and intermolecular electron-transfer (ET) states. We identify only minor changes of the LE excitation energies by interactions with the environment, but in drastic contrast to that, we found significant changes of the ET excitation energies. In the presence of the positively charged His365H(+), the ET excitation energies decrease, indicating facilitated electron transfer. In addition, the excitation energy of the second LE state, explaining the flavin's absorption at 380 nm, undergoes a 0.2 eV downshift. In contrast to the active-site protonation, reduced screening of the DNA phosphates increases the ET excitation energies but not the LE excitation energies. Accordingly, the electron affinities of the (6-4) photoproduct are significantly reduced, which should hinder electron transfer from the excited flavin. We also show that dynamic electron correlation accounted by the second order perturbation theory CASPT2 does not alter the energy trends obtained with the CASSCF method. Including the histidine side chain in the QM part enhances the effect of the histidine protonation on the ET energies. We also note that protonated His365H(+) can serve as an electron acceptor.