Abstract
Epidermal Growth Factor Receptor (EGFR), a member of the receptor tyrosine kinase family has shown to be implicated in the development and progression of various cancers due to mutations in the tyrosine kinase domain (TKD). It is important to understand the functional significance of amino acid variation occurring within TKD due to non-synonymous Single Nucleotide Polymorphism (nsSNPs). Therefore, we have evaluated the influence of nsSNPs on the structure of EGFR-TKD using computational methods. Out of 2,493 SNPs in the EGFR gene, only 41 were found to be non-synonymous. In silico evaluation of these nsSNPs using a sequence based SIFT tool and structure based PolyPhen algorithm revealed that 13 nsSNPs disrupted the conformation of EGFR-TKD. Protein stability analysis using CUPSAT, I-mutant2.0 and iPTree-STAB identified 6 mutants that are less stable than the wild structure. Thereafter, to evaluate the structural impact of 5 mutants (G719A, P733L, V742A, S768I and H773R) the molecular dynamics (MD) simulation for 2 ns was performed. The MD trajectories showed that the native EGFR was stabilized after 0.9 ns while the stability of mutants was achieved after longer simulation. The RMSF profile of P-loop and A-loop shows an increased flexibility for all the mutants. We also observed that the 3 mutants (V742A, P733L and H773R) showed large root mean square deviation (2.075, 2.59 and 2.752 Å respectively) compared to the native EGFR. Further docking studies indicate that gefitinib can be administered for combating cancer occurring due to presence of these mutations.
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Raghav, D., Sharma, V. & Agarwal, S.M. Structural investigation of deleterious non-synonymous SNPs of EGFR gene. Interdiscip Sci Comput Life Sci 5, 60–68 (2013). https://doi.org/10.1007/s12539-013-0149-x
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DOI: https://doi.org/10.1007/s12539-013-0149-x