Li Changrui, Zheng Yang, Jagodzinski Filip
Computer Science Department, Western Washington University, Bellingham, WA 98225, United States.
Bioinform Adv. 2024 Sep 27;4(1):vbae138. doi: 10.1093/bioadv/vbae138. eCollection 2024.
Understanding how amino acid insertion mutations affect protein structure can inform pharmaceutical efforts targeting diseases that are caused by protein mutants. simulation of mutations complements experiments performed on physical proteins which are time and cost prohibitive. We have computationally generated the exhaustive sets of two amino acid insertion mutations for five protein structures in the Protein Data Bank. To probe and identify how pairs of insertions affect structural stability and flexibility, we tally the count of hydrogen bonds and analyze a variety of metrics of each mutant. We identify hotspots where pairs of insertions have a pronounced effect, and study how amino acid properties such as size and type, and insertion into alpha helices, affect a protein's structure. The findings show that although there are some residues, Proline and Tryptophan specifically, which if inserted have a significant impact on the protein's structure, there is also a great deal of variance in the effects of the exhaustive insertions both for any single protein, and across the five proteins. That suggests that computational or otherwise quantitative efforts should consider large representative sample sizes especially when training models to make predictions about the effects of insertions.
The data underlying this article is available at https://multimute.cs.wwu.edu.
了解氨基酸插入突变如何影响蛋白质结构可为针对由蛋白质突变体引起的疾病的药物研发工作提供参考。突变模拟可补充对实体蛋白质进行的实验，而实体蛋白质实验既耗时又成本高昂。我们通过计算生成了蛋白质数据库中五个蛋白质结构的所有两个氨基酸插入突变的详尽集合。为了探究和识别插入对的影响如何影响结构稳定性和灵活性，我们统计了氢键的数量，并分析了每个突变体的各种指标。我们确定了插入对具有显著影响的热点，并研究了诸如大小和类型等氨基酸特性以及插入α螺旋如何影响蛋白质结构。研究结果表明，尽管存在一些残基，特别是脯氨酸和色氨酸，如果插入会对蛋白质结构产生重大影响，但对于任何单个蛋白质以及这五个蛋白质而言，详尽插入的影响也存在很大差异。这表明计算或其他定量研究应考虑大量具有代表性的样本量，尤其是在训练模型以预测插入影响时。
本文所依据的数据可在https://multimute.cs.wwu.edu获取。
