QM/MM studies reveal pathways leading to the quenching of the formation of thymine dimer photoproduct by flanking bases

Abstract

It is known that the formation of the photochemical product of thymine-thymine cyclobutane pyrimidine dimer (TT-CPD) formed upon UV excitation in DNA is significantly affected by the nature of the flanking bases, and that the oxidation potential of the flanking base correlates with the quenching of TT-CPD formation. However, the electronic details of this correlation have remained controversial. The quenching of thymine dimer formation exerted by flanking bases was suggested to be driven by both conformational and electronic effects. In the present study, we examine both of these effects using umbrella sampling and a quantum mechanical/molecular mechanical (QM/MM) approach for selected model systems. Our results demonstrate that a charge transfer (CT) state between the flanking base and the adjacent thymine base can provide a decay pathway for the population to escape from dimer formation, which eventually leads to the formation of an exciplex. The QM/MM vertical excitation energies also reveal that the oxidation potential of flanking bases correlates with the energy level of the CT state, thereby determining whether the CT state intersects with the state that can lead to dimer formation. The consistency between these results and experimentally obtained dimer formation rates implies that the quenching of dimer formation is mainly attributed to the decay pathway via the CT state. The present results further underline the importance of the electronic effects in quenching.

Photochemical Formation of Cyclobutane Pyrimidine Dimers in DNA through Electron Transfer from a Flanking Base

“…ET from an external moiety is believed to quench CPD formation, but, in contrast to what is known so far, here we demonstrate that a pathway initiated by ET from a flanking base can also lead to CPD formation. Furthermore, we also illustrate that the methylation of cytosine in T5mCG uses this pathway to enhance CPD formation ,…”

“…Exciplex formation has been considered as an effective quenching pathway competing with CPD formation ,,,. However, the exciplex found here works in the opposite way.…”

“…At this point, a question may arise about whether the exciplex found in other sequences can proceed through the same mechanism. In order to address this question, we examine GTT sequence where we had previously found CPD formation to be quenched via an exciplex formation . Interestingly, the exciplex in GTT displays relatively shorter distance (4.47 Å) between two radical centers, and no degeneracy is observed along the RC (Figure B and 2D).…”

“…Of special interest is T 2 . This state is termed dimer precursor (DP) state since it has been shown to be responsible for CPD formation . NTOs shown in Figure E also illustrate the bonding interactions.…”

Multiple Electronic and Structural Factors Control Cyclobutane Pyrimidine Dimer and 6–4 Thymine–Thymine Photodimerization in a DNA Duplex

“…Actually, it is known that CPD reactivity is affected by the nature of the flanking bases, especially purine . Furthermore, excitons delocalized over multiple bases are possible .…”