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首页> 外文期刊>Biochemistry >Impact of Rett Syndrome Mutations on MeCP2 MBD Stability
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Impact of Rett Syndrome Mutations on MeCP2 MBD Stability

机译：Rett综合征突变对MeCP2 MBD稳定性的影响

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Rett syndrome causing missense mutations in the methyl-CpG-binding domain (MBD) of methyl CpG-binding protein 2 (MeCP2) were investigated both in silico and in vitro to reveal their effect on protein stability. It is demonstrated that the vast majority of frequently occurring mutations in the human population indeed alter the MBD folding free energy by a fraction of a kcal/mol up to more than 1 kcal/mol. While the absolute magnitude of the change of the free energy is small, the effect on the MBD functionality may be substantial since the folding free energy of MBD is about 2 kcal/mol only. Thus, it is emphasized that the effect of mutations on protein integrity should be evaluated with respect to the wild-type folding free energy but not with the absolute value of the folding free energy change. Furthermore, it was observed that the magnitude of the effect is correlated neither with the burial of the mutation sites nor with the basic amino acid physicochemical property change. Mutations that strongly perturb the immediate structural features were found to have little effect on folding free energy, while very conservative mutations resulted in large changes of the MBD stability. This observation was attributed to the protein's ability to structurally relax and reorganize to reduce the effect of mutation. Comparison between in silk and in vitro results indicated that some Web servers perform relatively well, while the free energy perturbation approach frequently overpredicts the magnitude of the free energy change especially when a charged amino acid is involved.
机译：在计算机和体外研究了导致甲基CpG结合蛋白2（MeCP2）的甲基CpG结合域（MBD）错义突变的Rett综合征，以揭示其对蛋白质稳定性的影响。事实证明，人类中绝大多数经常发生的突变确实改变了MBD折叠自由能的几分之一kcal / mol，甚至超过了1 kcal / mol。尽管自由能变化的绝对量很小，但是由于MBD的折叠自由能仅为约2kcal / mol，因此对MBD功能性的影响可能很大。因此，要强调的是，突变对蛋白质完整性的影响应相对于野生型折叠自由能进行评估，而不应根据折叠自由能变化的绝对值进行评估。此外，已经观察到，效果的大小与突变位点的埋葬都不相关，也不与碱性氨基酸的理化性质变化相关。发现强烈干扰立即结构特征的突变对折叠自由能几乎没有影响，而非常保守的突变导致MBD稳定性的大变化。该观察结果归因于蛋白质在结构上放松和重组以减少突变影响的能力。真丝和体外结果之间的比较表明，某些Web服务器的性能相对较好，而自由能扰动方法经常高估了自由能变化的幅度，特别是当涉及带电荷的氨基酸时。

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