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Dynamic disequilibrium-based pathogenicity model in mutated pyrin's B30.2 domain-Casp1/p20 complex

Alaaeldin G Fayez1, Ghada Nour Eldeen1, Waheba A Zarouk1

  • 1Molecular Genetics and Enzymology Department, Human Genetics and Genome Research Institute, National Research Centre (NRC), Cairo, Egypt.

Journal, Genetic Engineering & Biotechnology
|February 22, 2022
PubMed
Abstract

Insights

Familial Mediterranean Fever (FMF) variants in B30.2/SPRY-casp1/p20 complexes cause inflammatory dysregulation. Molecular simulations reveal how specific mutations disrupt binding affinity, offering a new FMF pathogenicity model and potential colchicine dosage adjustments.

Area of Science:

  • Biochemistry
  • Computational Biology
  • Molecular Genetics

Background:

  • Familial Mediterranean Fever (FMF) is linked to B30.2 variants affecting pyrin's protein-protein interactions (PPI) and inflammatory regulation.
  • Pyrin-caspase-1 (casp1) interaction is crucial for inflammatory response; its dysregulation in FMF is associated with lower binding affinity in mutant B30.2 pyrin.
  • Understanding the impact of interface residues in the B30.2/SPRY-Casp1/p20 complex is key to elucidating FMF pathogenicity.

Purpose of the Study:

  • To investigate the effects of specific B30.2/SPRY-Casp1/p20 interface residues on complex dynamics and binding affinity.
  • To develop a computational model for FMF pathogenicity based on molecular mechanics simulations.
  • To identify potential biochemical markers for adjusting colchicine dosage in FMF patients.

Main Methods:

  • Molecular mechanics simulations were employed to analyze the B30.2/SPRY-Casp1/p20 complex.
  • In silico analysis was performed to assess the impact of Lys671Met, Ser703Ile, and Ala744Ser variants.
  • Binding affinity (∆G), dissociation constant (Kd), and root mean square deviation (RMSD) were calculated.

Main Results:

  • The studied variants (Lys671Met, Ser703Ile, Ala744Ser) significantly altered binding affinity and complex dynamics.
  • A shift in binding affinity and dissociation constant indicated dynamic disequilibrium in the p20-B30.2/SPRY complex.
  • The findings support a revised pathogenicity model for FMF.

Conclusions:

  • Molecular mechanics analysis revealed dynamic disequilibrium in the B30.2/SPRY-casp1/p20 complex for the studied variants, proposing a novel computational model for FMF pathogenicity.
  • The study identified specific biochemical markers that may aid in optimizing colchicine treatment for FMF patients.
  • These findings contribute to a deeper understanding of FMF pathogenesis and personalized therapeutic strategies.
Keywords:
B30.2 domainCasp1Familial Mediterenean FeverIn silico analysisPyrin

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