Lee Wook, Matsika Spiridoula
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.
Phys Chem Chem Phys. 2017 Jan 25;19(4):3325-3336. doi: 10.1039/c6cp05604k.
Cyclobutane pyrimidine dimers (CPDs) are the most commonly formed photochemical products when nucleic acids interact with UV radiation. In duplex DNA, the relative inflexible structure allows for only the cis, syn CPD isomer to be formed. G-quadruplex structures, however, have loops that are more flexible and allow for different orientations of the bases to interact. As a result, the highly unusual formation of an anti CPD has been observed in these structures. Due to the close proximity between two opposing loops containing the TTA sequence in two G-quadruplex structures (called "form-3" and "basket"), a high yield of anti CPD formation was expected in these structures. However, while significant yields of anti CPDs are observed in form-3, the anti CPD is hardly observed in the basket structure. To account for this inconsistency, we examine the process of anti CPD formation in form-3 and basket structures using simulations at the atomistic level. Here, we consider the conformational effect using MD simulations, which show whether the formation of the anti CPD is structurally feasible. Quantum mechanical/molecular mechanical (QM/MM) calculations of excited states are also used to consider the electronic effect by an adjacent guanine base which can quench the formation of the anti CPD through charge transfer (CT). Our results are in qualitative agreement with the experimental results, predicting a significant yield of the anti CPD in the form-3 structure and a negligible yield in the basket structure, while they also predict the formation of the cis, syn CPD between two opposing loops in form-3. Most importantly, our simulation results show that the yields of the anti CPD in the G-quadruplex are affected significantly by both conformational and electronic effects.
当核酸与紫外线辐射相互作用时，环丁烷嘧啶二聚体（CPD）是最常形成的光化学产物。在双链DNA中，相对刚性的结构仅允许形成顺式、同向CPD异构体。然而，G-四链体结构具有更灵活的环，允许碱基以不同方向相互作用。因此，在这些结构中观察到了极为罕见的反式CPD的形成。由于在两个G-四链体结构（称为“形式3”和“篮状”）中两个包含TTA序列的相对环之间距离很近，预计在这些结构中反式CPD的形成产率会很高。然而，虽然在形式3中观察到了显著产率的反式CPD，但在篮状结构中几乎未观察到反式CPD。为了解释这种不一致性，我们使用原子水平的模拟研究了形式3和篮状结构中反式CPD的形成过程。在这里，我们使用分子动力学（MD）模拟考虑构象效应，该模拟显示反式CPD的形成在结构上是否可行。还使用激发态的量子力学/分子力学（QM/MM）计算来考虑相邻鸟嘌呤碱基的电子效应，该效应可通过电荷转移（CT）淬灭反式CPD的形成。我们的结果与实验结果定性一致，预测形式3结构中反式CPD的产率很高，而篮状结构中的产率可忽略不计，同时还预测了形式3中两个相对环之间顺式、同向CPD的形成。最重要的是，我们的模拟结果表明，G-四链体中反式CPD的产率受构象和电子效应的显著影响。
