A Quantum Chemical Study of Photoinduced DNA Repair:  On the Splitting of Pyrimidine Model Dimers Initiated by Electron Transfer

Abstract

As a first step toward modeling the photoinduced repair of DNA, electronic structure calculations on the cleavage reaction of various pyrimidine dimers (uracil, thymine, and cytosine) as well as of their anion and cation radicals have been carried out using the AM1 UHF method. Two different paths of the splitting reaction have been studied by locating all stationary points. Along the first path, the opening of the cyclobutane ring is initiated by breaking the C5−C5‘ bond which leads to the formation of an intermediate, followed by the cleavage of the C6−C6‘ bond; along the second path, the two C−C‘ bonds are broken in reverse order. The results for the dimer anion radical favor a cleavage reaction along the first path while the second path is preferred for the cation radicals. Electron transfer to the dimers does not appreciably influence the enthalpy of the reaction for cycloreversion in the uracil and thymine dimers; however, it causes a dramatic reduction of the activation barrier for the cleavage reaction. In contrast, the reactivity of the cytosine dimer is only weakly affected by this electron uptake. Differences in the various reaction profiles are rationalized by invoking an energetic stabilization associated with the charge delocalization between fragments in the corresponding transition states. The calculated solvent effects evaluated by a dielectric continuum model show that the splitting reaction is sensitive to a polar environment. The reaction barriers of the splitting reaction are found to increase with the polarity of the medium, rationalizing the experimentally observed solvent effects on the dimer cleavage.

An AIMD Study of CPD Repair Mechanism in Water: Role of Solvent in Ring Splitting

“…6, 8, 23, 31, 32 During the entire splitting process we find a significant degree of charge delocalization onto the water. Before presenting results it is necessary to discuss several methodological difficulties associated with calculating the disposal of excess charge.…”

“…Rosch and coworkers 23 studied the evolution of the spin densities at the C5 and C5′ carbon atoms for the gas phase thymine dimer and proposed that as the C5-C5′ bond splits, the unpaired electron localizes at the C5′ carbon atom. In the left panel of Fig.…”

An AIMD Study of the CPD Repair Mechanism in Water: Reaction Free Energy Surface and Mechanistic Implications

“…Durbeej and Eriksson 55 conducted gas phase optimizations of the thymine dimer using DFT and found the breakage of the C5-C5′ bond to be barrierless. However Voityuk et al , 12 who conducted gas phase optimizations of the thymine dimer in continuum solvents at the AM1 level of theory, found significant barriers for the breakage of the C5-C5′ bond. The small barrier shown in Fig.…”

A Comparative Repair Study of Thymine- and Uracil-Photodimers with Model Compounds and a Photolyase Repair Enzyme

“…The presented measurements show that the two ªeclipsedº positioned thymine methyl groups do not increase the lability of the cyclobutane thymine dimer radical anion, which is in good agreement with recent calculations. [15,16] Based on our own ab initio calculations of the Mayer bond orders [41] of the neutral dimers and their radical anions, we suggest that the cleavage rates are influenced by stereoelectronic parameters. We believe that the better overlap between the p*-orbital of the C(4)O(4) double bond and the s*-C(5)ÀC(5')-bond orbital in the uracil dimer enhances its reductive cleavage vulnerability.…”

“…[13,14] Recent quantum chemical studies of cyclobutane uracil and thymine dimers support the destabilizing effect of the two methyl groups, but question significant changes of the dimer reactivity. [15,16] Ultrafast spectroscopic studies by Michel-Beyerle and calculations by Rösch and coworkers led to the conclusion that the different repair rates might be caused by a different binding geometry of uridine and thymidine photodimers within the enzyme active site. Different binding geometries could determine the repair rate by influencing the electron transfer processes between the FADH À cofactor and the corresponding lesion.…”