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Updated: May 12, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Structural investigation of deleterious non-synonymous SNPs of EGFR gene
Dhwani Raghav1, Vinay Sharma, Subhash Mohan Agarwal
1Bioinformatics Division, Institute of Cytology and Preventive Oncology, Noida 201301, India.
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.
Insights
Non-synonymous single nucleotide polymorphisms (nsSNPs) in the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase domain (TKD) can disrupt cancer progression. Computational analysis identified key EGFR-TKD nsSNPs affecting protein stability and structure, suggesting gefitinib as a potential treatment for associated cancers.
Area of Science:
- Molecular Biology
- Bioinformatics
- Cancer Research
Background:
- Epidermal Growth Factor Receptor (EGFR) is a receptor tyrosine kinase implicated in cancer development.
- Mutations within the EGFR tyrosine kinase domain (TKD) are common drivers of various cancers.
- Understanding the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) in EGFR-TKD is crucial for targeted therapies.
Purpose of the Study:
- To computationally evaluate the structural and functional impact of nsSNPs within the EGFR-TKD.
- To identify specific EGFR-TKD nsSNPs that significantly alter protein conformation and stability.
- To assess the potential of gefitinib in treating cancers associated with identified EGFR-TKD mutations.
Main Methods:
- In silico analysis of 2,493 EGFR SNPs to identify 41 nsSNPs.
- SIFT and PolyPhen algorithms for predicting the effect of nsSNPs on protein function.
- CUPSAT, I-mutant2.0, and iPTree-STAB for protein stability analysis.
- 2 ns molecular dynamics (MD) simulations for 5 selected mutants.
- Molecular docking studies with gefitinib.
Main Results:
- 13 nsSNPs were predicted to disrupt EGFR-TKD conformation.
- 6 mutants showed reduced protein stability compared to wild-type EGFR.
- MD simulations revealed increased flexibility in P-loop and A-loop for all mutants.
- 3 mutants (V742A, P733L, H773R) exhibited significant root mean square deviation.
- Docking studies suggest gefitinib efficacy against cancers with these specific mutations.
Conclusions:
- Specific nsSNPs in EGFR-TKD significantly impact protein structure, stability, and dynamics.
- The identified mutations represent potential therapeutic targets in EGFR-driven cancers.
- Gefitinib demonstrates potential as a treatment strategy for cancers harboring these specific EGFR-TKD mutations.
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