Thapa Bishnu, Munk Barbara H, Burrows Cynthia J, Schlegel H Bernhard
Chemistry Department, Wayne State University, Detroit, Michigan, 48202, USA.
Chemistry Department, University of Utah, Salt Lake City, Utah, 84112, USA.
Chemistry. 2017 Apr 27;23(24):5804-5813. doi: 10.1002/chem.201700231. Epub 2017 Apr 5.
Oxidation of guanine in the presence of lysine can lead to guanine-lysine cross-links. The ratio of the C4, C5 and C8 crosslinks depends on the manner of oxidation. Type II photosensitizers such as Rose Bengal and methylene blue can generate singlet oxygen, which leads to a different ratio of products than oxidation by type I photosensitizers or by one electron oxidants. Modeling reactions of singlet oxygen can be quite challenging. Reactions have been explored using CASSCF, NEVPT2, DFT, CCSD(T), and BD(T) calculations with SMD implicit solvation. The spin contamination in open-shell calculations were corrected by Yamaguchi's approximate spin projection method. The addition of singlet oxygen to guanine to form guanine endo- peroxide proceeds step-wise via a zwitterionic peroxyl intermediate. The subsequent barrier for ring closure is smaller than the initial barrier for singlet oxygen addition. Ring opening of the endoperoxide by protonation at C4-O is followed by loss of a proton from C8 and dehydration to produce 8-oxoG . The addition of lysine (modelled by methylamine) or water across the C5=N7 double bond of 8-oxoG is followed by acyl migration to form the final spiro products. The barrier for methylamine addition is significantly lower than for water addition and should be the dominant reaction channel. These results are in good agreement with the experimental results for the formation of guanine-lysine cross-links by oxidation by type II photosensitizers.
在赖氨酸存在的情况下，鸟嘌呤的氧化会导致鸟嘌呤 - 赖氨酸交联。C4、C5和C8交联的比例取决于氧化方式。诸如孟加拉玫瑰红和亚甲蓝之类的II型光敏剂可产生单线态氧，这导致产物比例与I型光敏剂或单电子氧化剂氧化产生的比例不同。模拟单线态氧的反应可能颇具挑战性。已使用CASSCF、NEVPT2、DFT、CCSD(T)和BD(T)计算并结合SMD隐式溶剂化来探索反应。开壳层计算中的自旋污染通过山口近似自旋投影方法进行校正。单线态氧加成到鸟嘌呤上形成鸟嘌呤内过氧化物是通过两性离子过氧中间体逐步进行的。随后的闭环势垒小于单线态氧加成的初始势垒。内过氧化物在C4 - O处质子化后开环，随后C8失去一个质子并脱水生成8 - 氧代鸟嘌呤（8 - oxoG）。赖氨酸（以甲胺模拟）或水加成到8 - oxoG的C5 = N7双键上，随后进行酰基迁移以形成最终的螺环产物。甲胺加成的势垒明显低于水加成的势垒，应该是主要的反应通道。这些结果与II型光敏剂氧化形成鸟嘌呤 - 赖氨酸交联的实验结果高度吻合。
