Theoretical study on the stability of N-glycosyl bonds:: Why does N7-platination not promote depurination?
Theoretical study on the stability of N-glycosyl bonds:: Why does N7-platination not promote depurination?
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DOI：
10.1021/ja017588
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发表时间：
2002-04-24
影响因子：
15
通讯作者：
Lippard, SJ
中科院分区：
文献类型：
--
作者：
Baik, MH;Friesner, RA;Lippard, SJ
通过密度泛函理论 (DFT) 结合溶剂化的连续处理，研究了 N7 位质子化或用顺铂修饰的鸟苷的脱嘌呤反应。质子化会加速脱嘌呤反应，而顺铂与 DNA 结合的初始产物 N7-铂化则不会。计算的反应能量分布表明，N7-铂化对过渡态的能量只有很小的影响，而质子化则将其降低了大约10 kcal mol(-1)。检查了涉及 N7-Pt/H 键合的轨道，并确定了两个取代鸟嘌呤之间的电子差异。自然键轨道分析、碎片轨道分析和扩展过渡态理论揭示了N7位置上不同电子取代基如何控制N9-C1'键的稳定性。 N7 取代鸟苷的电子结构的详细描述以及为获得这些系统的真实模型而开发的计算方案不仅解释了一个长期存在的谜团，而且为进一步研究了解顺铂与 DNA 的相互作用提供了指导。
The depurination reaction of guanosine, protonated or modified with cisplatin at the N7 position, has been studied by density functional theory (DFT), coupled with a continuum treatment of solvation. Protonation accelerates the depurination reaction whereas N7-platination, the initial product of cisplatin binding to DNA, does not. The computed reaction energy profiles demonstrate that N7-platination has only a minor effect on the energetics of the transition state, whereas protonation lowers it by similar to10 kcal mol(-1). The orbitals involved in N7-Pt/H bonding are examined, and electronic differences between the two substituted guanines are identified. Natural bond orbital analysis, fragment orbital analysis, and extended transition-state theory reveal how the electronically different substituents at the N7 position control the stability of the N9-C1' bond. The detailed description of the electronic structure of the N7-substituted guanosines and the computational protocol developed to obtain a realistic model for these systems not only explain a longstanding enigma but also provide guidelines for further studies toward understanding the interactions of cisplatin with DNA.