Novel topological methods are introduced to protein research. The aim is to identify hot-spot sites where a bifurcation can change the local topology of the protein backbone. Since the shape of a protein is intimately related to its biological function, a mutation that takes place at such a bifurcation hot-spot has an enhanced capacity to change the protein's biological function. The methodology applies to any protein but it is developed with the SARS-CoV-2 spike protein as a timely example. First, topological criteria are introduced to identify and classify potential mutation hot-spot sites along the protein backbone. Then, the expected outcome of a substitution mutation is estimated for a general class of hot-spots, by a comparative analysis of the backbone segments that surround the hot-spot sites. This analysis employs the statistics of commensurable amino acid fragments in the Protein Data Bank, in combination with general stereochemical considerations. It is observed that the notorious D614G substitution of the spike protein is a good example of such a mutation hot-spot. Several topologically similar examples are then analyzed in detail, some of them are even better candidates for a mutation hot-spot than D614G. The local topology of the recently observed N501Y mutation is also inspected, and it is found that this site is prone to a different kind of local topology changing bifurcation.

中文翻译：

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以SARS-CoV-2穗状蛋白为例，蛋白质中的局部拓扑，分叉和突变热点

新的拓扑方法被引入蛋白质研究。目的是确定分叉可以改变蛋白质主链局部拓扑的热点位置。由于蛋白质的形状与其生物学功能密切相关，因此在这样的分叉热点处发生的突变具有增强的改变蛋白质生物学功能的能力。该方法适用于任何蛋白质，但以SARS-CoV-2峰值蛋白为例进行了开发。首先，引入拓扑标准来识别和分类沿蛋白质骨架的潜在突变热点位点。然后，通过对围绕热点位置的主链节段进行比较分析，估计一般类别热点的替代突变的预期结果。该分析采用了蛋白质数据库中相应氨基酸片段的统计数据，并结合了常规立体化学因素。可以看出，臭豆蛋白的臭名昭著的D614G取代是这种突变热点的一个很好的例子。然后详细分析了几个拓扑相似的示例，其中一些示例比D614G更适合作为突变热点。还检查了最近观察到的N501Y突变的局部拓扑，发现该位点易于发生另一种改变分支的局部拓扑。然后详细分析了几个拓扑相似的示例，其中一些示例比D614G更适合作为突变热点。还检查了最近观察到的N501Y突变的局部拓扑，发现该位点倾向于发生另一种改变分支的局部拓扑。然后详细分析了几个拓扑相似的示例，其中一些示例比D614G更适合作为突变热点。还检查了最近观察到的N501Y突变的局部拓扑，发现该位点倾向于发生另一种改变分支的局部拓扑。