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IDP Force Fields Applied to Model PPII-Rich 33-mer Gliadin Peptides
María J Amundarain1,2, Agustín Vietri1, Verónica I Dodero2
1Departamento de Física, Instituto de Física del Sur (IFISUR), Universidad Nacional del Sur (UNS), CONICET, Avenida Leandro N. Alem 1253, B8000CPB Bahía Blanca, Argentina.
The Journal of Physical Chemistry. B
|March 8, 2023
Summary
Molecular dynamics simulations reveal the conformational ensembles of celiac disease (CD)-related gliadin peptides. These findings provide insights into the structural basis of CD pathogenesis and potential therapeutic targets.
Area of Science:
- Structural Biology
- Immunology
- Computational Chemistry
Background:
- Celiac disease (CD) is an autoimmune disorder affecting ~1% of the global population, triggered by gluten ingestion.
- The 33-mer gliadin peptide and its deamidated form (33-mer DGP) are key triggers of the adaptive immune response in CD.
- The structures of these intrinsically disordered peptides (IDPs) are not well understood.
Purpose of the Study:
- To explore the conformational landscape of the 33-mer gliadin peptide and 33-mer DGP using molecular dynamics (MD) simulations.
- To investigate the structural properties and secondary structure content of these peptides.
- To lay the groundwork for understanding peptide interactions relevant to CD pathogenesis.
Main Methods:
- Conformational sampling of the 33-mer peptides using MD simulations.
- Utilized two specialized force fields (Amber ff03ws and Amber ff99SB-disp) validated for IDPs.
- Analyzed simulation trajectories using clustering and calculated structural parameters like radius of gyration and secondary structure content.
Main Results:
- Both Amber force fields enabled extensive exploration of the conformational space, surpassing previous simulations.
- The dominant conformations were elongated, semi-elongated, and curved, characterized by large radius of gyration and solvent exposure.
- Polyproline II (PPII) secondary structure (58-73%) was consistently maintained, with a notable presence of β structures (11-23%).
Conclusions:
- MD simulations provide valuable insights into the structural ensembles of immunodominant celiac disease peptides.
- The Amber ff99SB-disp force field showed a higher propensity for exploring folded conformations.
- These findings are crucial for future studies on peptide interactions and the molecular mechanisms underlying celiac disease.
