In Silico Screening and Analysis of SNPs in Human ABCB1 (MDR1) Gene
ABCB1 (MDR1) is a transporter glycoprotein that has a major role in drug effluxes and resistance. Single nucleotide polymorphisms (SNPs) in ABCB1gene may affect protein expression, disease susceptibility and drug response, side effects and pharmacokinetics. The functional impact of most non-synonymous (ns) SNPs is still unclear. This study adopted a Structural bioinformatics approach to predict the effects of nsSNPs on ABCB1 structure and function. Methodology: The effects of coding nsSNPs were
... predicted by SIFT, PolyPhen-2, PANTHER, SNAP, PROVEAN, PhD-SNP and SNPs & GO. Prediction of protein stability changes was analyzed by I-Mutant. The conservation of amino acid positions in a protein was predicted by Consurf. NetSurfP was used to predict the surface accessibility of amino acid residue in protein structure. The impact of substitutions in protein was analyzed using Hope. Chimera was used to visualize changes in the protein 3D structure due to deleterious nsSNPs. Results: The nsSNPs of ABCB1 gene were retrieved from dbSNP database. nsSNPs were analyzed using SIFT and PolyPhen-2. To increase the accuracy of predictions, results of SIFT and PolyPhen-2 were joined and nsSNPs with PolyPhen score> 0.90 and SIFT< 0.05 were selected. Accordingly, three nsSNPs were classified as deleterious/damaging (rs28381902 (E566K), rs1128501 (G185V) and rs9282565 (A80E)). PANTHER, SNPs & GO, PhD-SNP, SNAP and PROVEAN confirmed the damaging effects of the first two nsSNPs, while the damaging effect of the third one was predicted only by PhD-SNP and SNAP. These three nsSNPs were predicted by I-Mutant as significantly decreasing the stability of the protein. ConSurf revealed that the three deleterious nsSNPs were located in intermediately/highly conserved regions. Conclusion: Structural bioinformatics approach proved capable of identifying the most damaging nsSNPs. This study predicted three nsSNPs in the ABCB1 gene as the most damaging. These nsSNPs, to the best of our knowledge, have not yet been investigated and therefore may be considered as candidates for association with diseases and drug response.