Dynamic behavior of DNA base pairs containing 8-oxoguanine
Dynamic behavior of DNA base pairs containing 8-oxoguanine
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DOI：
10.1021/ja052542s
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发表时间：
2005-10-12
影响因子：
15
通讯作者：
Simmerling, C
中科院分区：
文献类型：
--
作者：
Cheng, XL;Kelso, C;Simmerling, C
DNA 修复酶识别并选择性切除双链 DNA 中受损碱基的过程对于我们理解这些关键生物反应的机制至关重要。 8-氧鸟嘌呤 (8-oxoG) 是最常见的 DNA 氧化损伤形式；如果未修复，该病变会产生 G:C-T:A 突变。 DNA 损伤识别和修复的核心是碱基挤出，在这个过程中，受损的碱基损伤或在某些情况下其伙伴从螺旋中脱离，并与发生碱基切除的酶活性位点结合。双链 DNA 中 8-oxoG 采用的构象受到与该损伤相对的碱基的影响；当受损碱基与其同源修复酶结合时，也可能发生构象变化。我们对几个 13 聚体 DNA 双链体进行了无限制的分子动力学模拟。含有 G:C 和 8oxoG:C 对的低聚物在稳定的 B 型双链体中采用 Watson-Crick 几何结构； 8oxoG 显示出更高的局部和全局灵活性以及更低的碱基挤出障碍。含有 G:A 错配的双链体显示出更大的结构波动，并且未能采用明确的结构。对于被 DNA 糖基化酶 MutY 识别的 8oxoG:A 错配，受损的核苷经历自发且可重复的反→顺转换。顺式构象在热力学上是优选的。反构象中与 8oxoG O8 原子相关的空间位阻和不利静电是这一转变的主要驱动力。过渡事件遵循两种性质不同的途径。总体反->顺转换率和两条转换路径的相对概率取决于局部序列上下文。这些模拟表明，双链体的动态和平衡行为都会因氧化而发生变化。这些差异可能为酶对受损 DNA 的选择性作用提供有价值的新见解。
The process by which DNA repair enzymes recognize and selectively excise damaged bases in duplex DNA is fundamental to our mechanistic understanding of these critical biological reactions. 8-Oxoguanine (8-oxoG) is the most common form of oxidative DNA damage; unrepaired, this lesion generates a G:C-T:A mutation. Central to the recognition and repair of DNA damage is base extrusion, a process in which the damaged base lesion or, in some cases, its partner disengages from the helix and is bound to the enzyme's active site where base excision takes place. The conformation adopted by 8-oxoG in duplex DNA is affected by the base positioned opposite this lesion; conformational changes may also take place when the damaged base binds to its cognate repair enzyme. We performed unrestrained molecular dynamics simulations for several 13-mer DNA duplexes. Oligomers containing G:C and 8oxoG:C pairs adopted Watson-Crick geometries in stable B-form duplexes; 8oxoG showed increased local and global flexibility and a reduced barrier to base extrusion. Duplexes containing the G:A mismatch showed much larger structural fluctuations and failed to adopt a well-defined structure. For the 8oxoG:A mismatch that is recognized by the DNA glycosylase MutY, the damaged nucleoside underwent spontaneous and reproducible anti -> syn transitions. The syn conformation is thermodynamically preferred. Steric hindrance and unfavorable electrostatics associated with the 8oxoG O8 atom in the anti conformation were the major driving forces for this transition. Transition events follow two qualitatively different pathways. The overall anti -> syn transition rate and relative probability of the two transition paths were dependent on local sequence context. These simulations indicate that both the dynamic and equilibrium behavior of the duplex change as a result of oxidation; these differences may provide valuable new insight into the selective action of enzymes on damaged DNA.