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Screening of mutations affecting protein stability and dynamics of FGFR1-A simulation analysis
C George Priya Doss1, B Rajith1, Nimisha Garwasis1
1Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
Abstract:
Single amino acid substitutions in Fibroblast Growth Factor Receptor 1 (FGFR1) destabilize protein and have been implicated in several genetic disorders like various forms of cancer, Kallamann syndrome, Pfeiffer syndrome, Jackson Weiss syndrome, etc. In order to gain functional insight into mutation caused by amino acid substitution to protein function and expression, special emphasis was laid on molecular dynamics simulation techniques in combination with in silico tools such as SIFT, PolyPhen 2.0, I-Mutant 3.0 and SNAP. It has been estimated that 68% nsSNPs were predicted to be deleterious by I-Mutant, slightly higher than SIFT (37%), PolyPhen 2.0 (61%) and SNAP (58%). From the observed results, P722S mutation was found to be most deleterious by comparing results of all in silico tools. By molecular dynamics approach, we have shown that P722S mutation leads to increase in flexibility, and deviated more from the native structure which was supported by the decrease in the number of hydrogen bonds. In addition, biophysical analysis revealed a clear insight of stability loss due to P722S mutation in FGFR1 protein. Majority of mutations predicted by these in silico tools were in good concordance with the experimental results.
Insights
Single amino acid substitutions in Fibroblast Growth Factor Receptor 1 (FGFR1) can cause genetic disorders. The P722S mutation destabilizes FGFR1, leading to increased protein flexibility and loss of function.
Area of Science:
- Biochemistry
- Genetics
- Computational Biology
Background:
- Single amino acid substitutions in Fibroblast Growth Factor Receptor 1 (FGFR1) destabilize the protein.
- These destabilizing mutations are linked to various genetic disorders, including cancers and syndromes like Kallmann, Pfeiffer, and Jackson-Weiss.
Purpose of the Study:
- To investigate the functional impact of amino acid substitutions on FGFR1 protein function and expression.
- To identify specific mutations that lead to protein destabilization and disease.
Main Methods:
- Utilized in silico tools: SIFT, PolyPhen 2.0, I-Mutant 3.0, and SNAP to predict mutation effects.
- Employed molecular dynamics (MD) simulations to analyze the structural and dynamic changes caused by mutations.
- Conducted biophysical analysis to assess protein stability.
Main Results:
- In silico tools predicted a high percentage of deleterious mutations (I-Mutant: 68%, PolyPhen 2.0: 61%, SNAP: 58%, SIFT: 37%).
- The P722S mutation was identified as the most deleterious across all tested in silico tools.
- MD simulations revealed that P722S increases FGFR1 flexibility, structural deviation, and reduces hydrogen bonds, indicating loss of stability.
- Biophysical analysis confirmed reduced stability of FGFR1 due to the P722S mutation.
Conclusions:
- The P722S mutation significantly destabilizes FGFR1, impacting its function and potentially causing genetic disorders.
- In silico predictions showed good concordance with experimental results, validating their utility in studying mutation effects.
- Understanding mutation-induced FGFR1 destabilization is crucial for diagnosing and potentially treating associated genetic disorders.
