Elucidating Which Pairwise Mutations Affect Protein Stability: An Exhaustive Big Data Approach
Elucidating Which Pairwise Mutations Affect Protein Stability: An Exhaustive Big Data Approach
复制标题
阐明哪些成对突变影响蛋白质稳定性：详尽的大数据方法
DOI：
10.1109/compsac.2018.00078
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
F. Jagodzinski
中科院分区：
文献类型：
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作者：
Nicholas Majeske;F. Jagodzinski
多肽链中特定的氨基酸序列决定了蛋白质的三维结构，从而决定了蛋白质的功能。对涉及氨基酸替代的物理蛋白质进行的突变实验提供了洞察力，使制药公司能够设计出对抗各种致衰性疾病的药物。然而，这种潮湿的实验室工作是令人望而却步的，因为即使是研究单一突变的影响也可能需要数周的工作。已经开发了对单一突变的影响进行详尽筛选的计算方法，但由于需要分析大量的突变蛋白质结构，因此无法对所有多重突变的影响进行系统的、详尽的筛选。在这项工作中，我们激发并演示了一种概念验证方法，用于在电子计算机实验中进行，其中我们生成了所有可能的突变结构，其中两个氨基酸替换为三个蛋白质，分别有46，67和99个残基；对于最大的蛋白质，我们在电子计算机中生成了1,751,211个突变。我们利用一种有效的组合算法来评估突变蛋白质结构之间的突变的影响。我们还制作了几个突变指标的热图，以便于根据这些氨基酸替代如何影响蛋白质的灵活性来识别蛋白质中哪些氨基酸对蛋白质稳定性的影响最大。
The specific sequence of amino acids in a polypeptide chain dictates the three dimensional structure, and hence function, of a protein. Mutagenesis experiments on physical proteins involving amino acid substitutions provide insights enabling pharmaceutical companies to design medicines to combat a variety of debilitating diseases. However such wet lab work is prohibitive, because even studying the effects of a single mutation may require weeks of work. Computational approaches for performing exhaustive screens of the effects of single mutations have been developed, but methods for conducting a systematic, exhaustive screen of the effects of all multiple mutations are not available due to the large number of mutant protein structures that would need to be analyzed. In this work we motivate and demonstrate a proof of concept approach for conducting in silico experiments in which we generate all possible mutant structures with 2 amino acid substitutions for three proteins with 46, 67, and 99 residues; for the largest protein we in silico generate 1,751,211 mutants. We leverage an efficient combinatorial algorithm to assess the effects of the mutations among the mutant protein structures. We also produce heat maps for several mutation metrics to facilitate identifying which pairs of amino acid in a protein have the greatest impact on protein stability based on how those amino acid substitutions affect the protein's flexibility.