Xu Duoduo, Shao Qiqi, Zhou Chen, Mahmood Arif, Zhang Jizhou
Oncology Department, Wenzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou 325000, China.
Department of Nursing, Central Health Center of Zeya Town, Ouhai District, Wenzhou 325000, China.
ACS Omega. 2023 Apr 3;8(14):13362-13370. doi: 10.1021/acsomega.3c00804. eCollection 2023 Apr 11.
The gene belongs to the RAS family and codes for 188 amino acid residues of KRAS protein, with a molecular mass of 21.6 kD. Non-synonymous single-nucleotide polymorphisms (nsSNPs) have been identified within the coding region in which some are associated with different diseases. However, structural changes are not well defined yet. In this study, we first categorized SNPs in the coding area and then used computational methods to determine their impact on the protein structure and stability. In addition, the three-dimensional model of KRAS was taken from the Protein Data Bank for structural modeling. Furthermore, genomic data were extracted from a variety of sources, including the 1000 Genome Project, dbSNPs, and ENSEMBLE, and assessed through methods. Based on various tools used in this study, 10 out of 48 missense SNPs with rsIDs were found deleterious. The substitution of alanine for proline at position 146 pushed several residues toward the center of the protein. Arginine instead of leucine has a minor effect on protein structure and stability. In addition, the substitution of proline for leucine at the 34th position disrupted the structure and led to a bigger size than the wild-type protein, hence interrupting the protein interaction. Using the well-intended computational approach and applying several bioinformatic tools, we characterized and identified most damaging nsSNPs and further explored the structural dynamics and stability of KRAS protein.
该基因属于RAS家族，编码KRAS蛋白的188个氨基酸残基，分子量为21.6 kD。已在编码区域内鉴定出非同义单核苷酸多态性（nsSNPs），其中一些与不同疾病相关。然而，其结构变化尚未明确界定。在本研究中，我们首先对编码区的SNP进行分类，然后使用计算方法确定它们对蛋白质结构和稳定性的影响。此外，KRAS的三维模型取自蛋白质数据库进行结构建模。此外，基因组数据从包括千人基因组计划、dbSNPs和ENSEMBLE在内的多种来源提取，并通过方法进行评估。基于本研究中使用的各种工具，发现48个带有rsID的错义SNP中有10个是有害的。第146位的丙氨酸取代脯氨酸使几个残基向蛋白质中心移动。精氨酸取代亮氨酸对蛋白质结构和稳定性有较小影响。此外，第34位的脯氨酸取代亮氨酸破坏了结构，导致蛋白质比野生型更大，从而中断了蛋白质相互作用。使用精心设计的计算方法并应用多种生物信息学工具，我们对最具破坏性的nsSNPs进行了表征和鉴定，并进一步探索了KRAS蛋白的结构动力学和稳定性。
