Computational Screening and Analysis of Lung Cancer Related Non-Synonymous Single Nucleotide Polymorphisms on the Human Kirsten Rat Sarcoma Gene

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-05, Vol.24 (10), p.1951
• Main Authors: Wang, Qiankun, Mehmood, Aamir, Wang, Heng, Xu, Qin, Xiong, Yi, Wei, Dong-Qing
• Format: Article
• Language: English
• Subjects: Amino acid sequence; Amino Acid Substitution - genetics; Amino acids; Biomarkers, Tumor - chemistry; Biomarkers, Tumor - genetics; Computational Biology; Computer applications; Crystal structure; Deoxyribonucleic acid; DNA; Dynamic structural analysis; functional effect; Genomes; Humans; K-Ras protein; Lung cancer; Lung Neoplasms - diagnosis; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Molecular Conformation; Molecular dynamics; Molecular Dynamics Simulation; Mutants; Mutation; Mutation - genetics; Nucleotide sequence; Nucleotides; Polymorphism, Single Nucleotide - genetics; Proteins; Proto-Oncogene Proteins p21(ras) - chemistry; Proto-Oncogene Proteins p21(ras) - genetics; Research methodology; Sarcoma; Simulation; Single-nucleotide polymorphism; Software; structural analysis; Structural stability; Structure-Activity Relationship; Structure-function relationships; Support vector machines
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24101951

The human KRAS (Kirsten rat sarcoma) is an oncogene, involved in the regulation of cell growth and division. The mutations in the KRAS gene have the potential to cause normal cells to become cancerous in human lungs. In the present study, we focus on non-synonymous single nucleotide polymorphisms (nsSNPs), which are point mutations in the DNA sequence leading to the amino acid variants in the encoded protein. To begin with, we developed a pipeline to utilize a set of computational tools in order to obtain the most deleterious nsSNPs (Q22K, Q61P, and Q61R) associated with lung cancer in the human KRAS gene. Furthermore, molecular dynamics simulation and structural analyses of the 3D structures of native and mutant proteins confirmed the impact of these nsSNPs on the stability of the protein. Finally, the experimental results demonstrated that the structural stability of the mutant proteins was worse than that of the native protein. This study provides significant guidance for narrowing down the number of KRAS mutations to be screened as potential diagnostic biomarkers and to better understand the structural and functional mechanisms of the KRAS protein.