Prechemistry versus preorganization in DNA replication fidelity.
Prechemistry versus preorganization in DNA replication fidelity.
复制标题
DOI：
10.1002/prot.23128
复制
发表时间：
2011-10
影响因子：
2.9
通讯作者：
Warshel, Arieh
中科院分区：
文献类型：
--
作者：
Prasad, B. Ram;Warshel, Arieh
关键词：
通过计算模拟探讨了核苷酸插入催化的分子起源和DNA聚合酶的保真度。特别注意审查援引化学前效应、检查点概念和动力学效应的建议的有效性。模拟重现了Pol β中观察到的保真度，从正确(R)和错误(W)核苷酸的相关观察到的x射线结构开始。R和W系统的自由能面也使我们能够分析关于保真度起源的不同建议，并得出几个重要的结论。发现通过适当取样得到的平均力势（PMF）不支持基于QM/MM的预化学势垒建议。此外，通过重整化方法对动力学建议的检验表明，从开放到封闭构型的运动对催化或保真度没有贡献。最后，我们讨论和分析了诱导拟合的概念，并表明，尽管它很重要，但它并不能解释保真度。也就是说，保真度显然是由于化学位点的预组织发生了变化，这是由于它对W碱基而不是R碱基结合时结合位点重组的响应。此外，由于问题是在化学过渡状态下与酶-底物(ES)/DNA复合物相关的屏障，而不是该复合物形成的路径（除非该路径涉及速率决定步骤），因此在讨论保真度时调用检查点也没有用。
The molecular origin of nucleotide insertion catalysis and fidelity of DNA polymerases is explored by means of computational simulations. Special attention is paid to the examination of the validity of proposals that invoke prechemistry effects, checkpoints concepts and dynamical effects. The simulations reproduce the observed fidelity in Pol β, starting with the relevant observed x-ray structures of the complex with the right (R) and wrong (W) nucleotides. The generation of free energy surfaces for the R and W systems also allowed us to analyze different proposals about the origin of the fidelity and to reach several important conclusions. It is found that the potential of mean force (PMF) obtained by proper sampling does not support QM/MM based proposals of prechemistry barriers. Furthermore, examination of dynamical proposals by the renormalization approach indicates that the motions from open to close configurations do not contribute to catalysis or fidelity. Finally we discuss and analyze the induced fit concept and show that, despite its importance, it does not explain fidelity. That is, the fidelity is apparently due to change in the preorganization of the chemical site, due to its response to the binding site reorganization in the binding of the W instead of the R base. Furthermore, since the issue is the barrier associated with the enzyme-substrate (ES)/DNA complex at the chemical transition state and not the path to this complex formation (unless this path involves rate determining steps), it is also not useful to invoke checkpoints while discussing fidelity.
登录
查看更多内容
影响因子：
15
作者：
Alberts, Ian L.;Wang, Yanli;Schlick, Tamar
通讯作者：
Schlick, Tamar
影响因子：
5.7
作者：
Batra, VK;Beard, WA;Wilson, SH
通讯作者：
Wilson, SH
影响因子：
5.7
作者：
Bondar, AN;Elstner, M;Fischer, S
通讯作者：
Fischer, S
影响因子：
4.1
作者：
Ahn, JW;Kraynov, VS;Tsai, MD
通讯作者：
Tsai, MD
影响因子：
56.9
作者：
Boehr, David D.;McElheny, Dan;Wright, Peter E.
通讯作者：
Wright, Peter E.