Predicting the impact of deleterious mutations in the protein kinase domain of FGFR2 in the context of function, structure, and pathogenesis--a bioinformatics approach
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Published on: August 24, 2013
George Priya Doss C1, B Rajith, Chiranjib Chakraborty
1Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India. georgepriyadoss@vit.ac.in
Abstract:
Fibroblast growth factor receptor 2 (FGFR2) controls a wide range of biological functions by regulating the cellular proliferation, survival, migration and differentiation. A growing body of preclinical data demonstrated that deregulation of the FGFR signalling through genetic modification was observed in various types of cancers. However, the extent to which genetic modifications interfere with gene regulation and their involvement in cancer susceptibility remains largely unknown. In this work, we performed in silico profiling of harmful non-synonymous single nucleotide polymorphisms (SNPs) in the protein kinase domain of FGFR2. Tolerance index, position-specific independent count score, change in free energy score (ΔΔG), Eris and FoldX indicated that seven mutations were found to be deleterious and may alter the protein function and structure. Furthermore, based on physico-chemical properties, two mutations K659N and R747H were found to be most deleterious in protein kinase domain and taken for further structural analysis. Docking study showed a complete loss of binding affinity followed by interference in hydrogen bonding and surrounding residues due to K659N and R747H mutations. In order to elucidate the mechanism behind the impact of mutation that can generate a ripple effect throughout the protein structure and ultimately affect the function, in-depth molecular dynamics simulation and principal component analysis were performed. The obtained results indicate that K659N and R747H mutations have a distinct effect on the dynamic behaviour of FGFR2 protein. Our strategy may be helpful for understanding SNP effects on proteins with function and their role in human genetic diseases and for the development of novel pharmacological strategies.
Insights
Harmful mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) protein kinase domain can disrupt its function, potentially increasing cancer risk. Specific mutations, K659N and R747H, were identified as particularly damaging, affecting protein structure and dynamics.
Area of Science:
- Genetics
- Molecular Biology
- Bioinformatics
Background:
- Fibroblast Growth Factor Receptor 2 (FGFR2) is crucial for cell functions like proliferation and survival.
- Deregulation of FGFR signaling via genetic modification is implicated in various cancers.
- The precise impact of genetic modifications on gene regulation and cancer susceptibility is not fully understood.
Purpose of the Study:
- To identify and analyze harmful non-synonymous single nucleotide polymorphisms (SNPs) within the FGFR2 protein kinase domain.
- To investigate the structural and functional consequences of identified mutations.
- To elucidate the molecular mechanisms by which FGFR2 mutations influence protein dynamics and function.
Main Methods:
- In silico profiling using tools like Tolerance index, PISS, ΔΔG, Eris, and FoldX to predict deleterious mutations.
- Physico-chemical property analysis to identify the most harmful mutations.
- Molecular docking studies to assess binding affinity and interaction changes.
- Molecular dynamics simulations and principal component analysis to evaluate effects on protein dynamics.
Main Results:
- Seven mutations in the FGFR2 protein kinase domain were predicted to be deleterious.
- Mutations K659N and R747H were identified as the most damaging based on physico-chemical properties.
- Docking studies revealed a loss of binding affinity and disrupted hydrogen bonding for K659N and R747H.
- Molecular dynamics simulations demonstrated distinct alterations in the dynamic behavior of FGFR2 due to these mutations.
Conclusions:
- The identified mutations, particularly K659N and R747H, can significantly alter FGFR2 protein structure and function.
- These findings contribute to understanding the role of SNPs in protein function and human genetic diseases.
- The study provides a basis for developing novel pharmacological strategies targeting FGFR2 in cancer therapy.
