In Silico Analysis of nsSNPs of Human KRAS Gene and Protein Modeling Using Bioinformatic Tools

Duoduo Xu; Qiqi Shao; Chen Zhou; Arif Mahmood; Jizhou Zhang

doi:10.1021/acsomega.3c00804

In Silico Analysis of nsSNPs of Human KRAS Gene and Protein Modeling Using Bioinformatic Tools

ACS Omega. 2023 Apr 3;8(14):13362-13370. doi: 10.1021/acsomega.3c00804. eCollection 2023 Apr 11.

Authors

Duoduo Xu¹, Qiqi Shao², Chen Zhou³, Arif Mahmood⁴, Jizhou Zhang¹

Affiliations

¹ Oncology Department, Wenzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou 325000, China.
² Department of Nursing, Central Health Center of Zeya Town, Ouhai District, Wenzhou 325000, China.
³ Ultrasonography Department, Wenzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou 325099, China.
⁴ Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.

Abstract

The KRAS 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 KRAS 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 in silico 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.