Computational Screening Deleterious Non-Synonymous Single Nucleotide Polymorphisms And Molecular Dynamic Simulation Of Lung Cancer Associated Mutations In KRAS Gene

In recent years,the incidence of cancer has been increasing.Lung cancer is the most common type of cancer and is also one of the major types of cancer that cause death.Non-small cell lung cancer(NSCLC)is the significant type in lung cancer.Previous studies have found that lung cancer is mainly caused by the accumulation of genomic variation.Among them,KRAS gene is the most significant and common mutation gene in lung cancer.Single nucleotide polymorphism(SNPs)is a kind of genetic variation,and the single nucleotide variation at the genome level will cause DNA sequence polymorphism.Single nucleotide polymorphisms(SNPs)are the most general heritable variation in human,it accounting for more than 80% of all-known polymorphisms.SNPs are ubiquitous in human genome.There is an SNP mutation each 200-300 BP in the entire human genome.Among various SNPs mutation types,non-synonymous substitution(nsSNPs)those who occurring in exon regions may change the mechanism of transcription and translation,and then the secondary sequence of proteins is changed.Thus,the original function and gene regulation of protein are affected;further many diseases of organisms are caused by this.Therefore,nsSNPs are very deleterious single nucleotide mutations and may lead to a variety of diseases in human.Previous studies have shown that the experimental approach is unable to explore the molecular mechanism,and how the mutations affect KRAS gene and protein.In this study,the mutation of nsSNPs associated with lung cancer in KRAS gene was studied by computational screening and molecular dynamics approach,and solved the above problem.We used highly trained and optimized computational algorithms to screen deleterious nsSNPs associated with lung cancer in KRAS gene.Then,molecular dynamics approach was used to simulate the structure of native and mutant proteins.In our study,we found that this three mutations: rs121913236(Q22K),rs121913240(Q61P and Q61R)are deleterious mutations associated with lung cancer in KRAS gene.According to screening results,the native protein structure and the mutant proteins structure were constructed,and the molecular dynamics simulation was carried out,respectively.After obtaining the simulation results,the four protein dynamic trajectories were analyzed by RMSD,RMSF,Rg,SASA,PCA and DSSP analysis.All the results showed that the structural stability of the mutant proteins was worse than the native protein.We all know that the stability of protein affects the activity and function of protein.Mutations altered the structural stability of protein and makes protein cannot perform its original biological function,so that cause a series of diseases.Therefore,the results of our study are very important.It can further help researchers understand how the deleterious nsSNPs in KRAS gene can affect the proteins structure at the molecular level,and provide guidance for future research on the experimental work of searching for treatment methods of lung cancer from KRAS gene.