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Screening of mutations affecting protein stability and dynamics of FGFR1 — A simulation analysis

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Superimposition of native and mutant modeled structures (cartoon shape) of FGFR1.A. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid glycine (red color) at position 513 in PDB ID 3RHX of FGFR1.B. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid methionine (red color) at position 607 in PDB ID 3RHX of FGFR1.C. Superimposed structure of native amino acid proline in sphere shape (blue color) with mutant amino acid serine (red color) at position 722 in PDB ID 3RHX of FGFR1.
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f0005: Superimposition of native and mutant modeled structures (cartoon shape) of FGFR1.A. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid glycine (red color) at position 513 in PDB ID 3RHX of FGFR1.B. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid methionine (red color) at position 607 in PDB ID 3RHX of FGFR1.C. Superimposed structure of native amino acid proline in sphere shape (blue color) with mutant amino acid serine (red color) at position 722 in PDB ID 3RHX of FGFR1.

Mentions: Each amino acid has unique size, charge and hydrophobicity value. SNP with ID rs77988343 results in the mutation of valine to glycine at position 513. The mutant residue is smaller than the wild type residue which leads to an empty space in the core of the protein. This mutation might cause loss of hydrophobic interactions in the core of the protein. Substitution of valine to glycine results in a slight worsening of ProSA-web z-score, from − 9.13 to − 9.05, while there was no change in Verify 3D score (0.81). The total energy of native protein after energy minimization using NOMAD-Ref was − 890,123.34 kcal/mol, and for the mutant protein was found to be − 889,931.09 kcal/mol. The RMSD value between native and mutant modeled protein was 1.01 Å. The superimposed structures of the native protein 3RHX (chain A) with the mutant model is shown in Fig. 1A.


Screening of mutations affecting protein stability and dynamics of FGFR1 — A simulation analysis
Superimposition of native and mutant modeled structures (cartoon shape) of FGFR1.A. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid glycine (red color) at position 513 in PDB ID 3RHX of FGFR1.B. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid methionine (red color) at position 607 in PDB ID 3RHX of FGFR1.C. Superimposed structure of native amino acid proline in sphere shape (blue color) with mutant amino acid serine (red color) at position 722 in PDB ID 3RHX of FGFR1.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121281&req=5

f0005: Superimposition of native and mutant modeled structures (cartoon shape) of FGFR1.A. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid glycine (red color) at position 513 in PDB ID 3RHX of FGFR1.B. Superimposed structure of native amino acid valine in sphere shape (blue color) with mutant amino acid methionine (red color) at position 607 in PDB ID 3RHX of FGFR1.C. Superimposed structure of native amino acid proline in sphere shape (blue color) with mutant amino acid serine (red color) at position 722 in PDB ID 3RHX of FGFR1.
Mentions: Each amino acid has unique size, charge and hydrophobicity value. SNP with ID rs77988343 results in the mutation of valine to glycine at position 513. The mutant residue is smaller than the wild type residue which leads to an empty space in the core of the protein. This mutation might cause loss of hydrophobic interactions in the core of the protein. Substitution of valine to glycine results in a slight worsening of ProSA-web z-score, from − 9.13 to − 9.05, while there was no change in Verify 3D score (0.81). The total energy of native protein after energy minimization using NOMAD-Ref was − 890,123.34 kcal/mol, and for the mutant protein was found to be − 889,931.09 kcal/mol. The RMSD value between native and mutant modeled protein was 1.01 Å. The superimposed structures of the native protein 3RHX (chain A) with the mutant model is shown in Fig. 1A.

View Article: PubMed Central - PubMed

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.

No MeSH data available.