Drug Design & Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai 201203, PR China.
Chemphyschem. 2010 Jan 18;11(1):175-81. doi: 10.1002/cphc.200900656.
To elucidate the role of guanosine in DNA strand breaks caused by low-energy electrons (LEEs), theoretical investigations of the LEE attachment-induced C-O sigma-bonds and N-glycosidic bond breaking of 2'-deoxyguanosine-3',5'-diphosphate (3',5'-dGMP) were performed using the B3LYP/DZP++ approach. The results reveal possible reaction pathways in the gas phase and in aqueous solutions. In the gas phase LEEs could attach to the phosphate group adjacent to the guanosine to form a radical anion. However, the small vertical detachment energy (VDE) of the radical anion of guanosine 3',5'-diphosphate in the gas phase excludes either C-O bond cleavage or N-glycosidic bond breaking. In the presence of the polarizable surroundings, the solvent effects dramatically increase the electron affinities of the 3',5'-dGDP and the VDE of 3',5'-dGDP(-). Furthermore, the solvent-solute interactions greatly reduce the activation barriers of the C-O bond cleavage to 1.06-3.56 kcal mol(-1). These low-energy barriers ensure that either C(5')-O(5') or C(3')-O(3') bond rupture takes place at the guanosine site in DNA single strands. On the other hand, the comparatively high energy barrier of the N-glycosidic bond rupture implies that this reaction pathway is inferior to C-O bond cleavage. Qualitative agreement was found between the theoretical sequence of the bond breaking reaction pathways in the PCM model and the ratio for the corresponding bond breaks observed in the experiment of LEE-induced damage in oligonucleotide tetramer CGTA. This concord suggests that the influence of the surroundings in the thin solid film on the LEE-induced DNA damage resembles that of the solvent.
为了阐明鸟嘌呤核苷在低能电子（LEE）引起的 DNA 链断裂中的作用，使用 B3LYP/DZP++方法对 LEE 附加诱导的 C-O σ 键和 N-糖苷键断裂的 2'-脱氧鸟苷-3'，5'-二磷酸酯（3'，5'-dGMP）进行了理论研究。结果揭示了气相和水溶液中的可能反应途径。在气相中，LEE 可以附着在鸟嘌呤核苷相邻的磷酸基团上形成自由基阴离子。然而，鸟苷 3'，5'-二磷酸酯自由基阴离子的小垂直离解能（VDE）排除了 C-O 键的断裂或 N-糖苷键的断裂。在极化环境的存在下，溶剂效应极大地增加了 3'，5'-dGDP 的电子亲合势和 3'，5'-dGDP(-)的 VDE。此外，溶剂-溶质相互作用大大降低了 C-O 键断裂的活化能垒至 1.06-3.56 kcal mol(-1)。这些低能量垒确保了在 DNA 单链中的鸟嘌呤核苷位点发生 C(5')-O(5')或 C(3')-O(3')键断裂。另一方面，N-糖苷键断裂的相对高能量垒意味着该反应途径不如 C-O 键断裂。在 PCM 模型中，键断裂反应途径的理论顺序与实验中观察到的 LEE 诱导寡核苷酸四聚体 CGTA 损伤中相应键断裂的比例之间存在定性一致性。这种一致性表明，在薄膜中环境对 LEE 诱导的 DNA 损伤的影响类似于溶剂的影响。
