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Front. Immunol. | doi: 10.3389/fimmu.2019.02483

ADDENDUM: p31-43 Gliadin Peptide Forms Oligomers and Induces NLRP3 Inflammasome/Caspase 1- Dependent Mucosal Damage in Small Intestine.

Exequiel Barrera1,  Fernando G. Chirdo2 and  Sergio Pantano1*
  • 1Institut Pasteur de Montevideo, Uruguay
  • 2National University of La Plata, Argentina

ADDENDUM: p31-43 Gliadin Peptide Forms Oligomers and Induces NLRP3 Inflammasome/Caspase 1- Dependent Mucosal Damage in Small Intestine.

Exequiel Barrera1, Fernando Chirdo2 and Sergio Pantano1*
1 Biomolecular Simulations Group, Institut Pasteur de Montevideo, Montevideo, Uruguay, 2 Instituto de Estudios Inmunológicos y Fisiopatológicos (UNLP-CONICET), Facultad de Ciencias Exactas, La Plata, Argentina.

A commentary on: p31-43 Gliadin Peptide Forms Oligomers and Induces NLRP3 Inflammasome/Caspase 1- Dependent Mucosal Damage in Small Intestine. By María Florencia Gómez Castro, Emanuel Miculán, María Georgina Herrera, Carolina Ruera, Federico Perez, Eduardo Daniel Prieto, Exequiel Barrera, Sergio Pantano, Paula Carasi and Fernando Gabriel Chirdo.
In our recent publication p31-43 Gliadin Peptide Forms Oligomers and Induces NLRP3 Inflammasome/Caspase 1- Dependent Mucosal Damage in Small Intestine” (1) we showed by a combination of experimental and simulation techniques that the peptide p31-43 gliadin has an intrinsic propensity to form oligomers, which trigger the NLRP3 inflammasome, resulting in intestinal inflammation and pathology. In particular, molecular simulations performed with the SIRAH force field (2), showed that isolated p31-43 peptides exhibit a broad conformational dynamic with some PPII component, mostly related to the presence of Pro36 and Pro42. Simulation of multiple replicas showed a spontaneous tendency to aggregation with a concomitant increase in the PPII content for Pro38 and Pro 39.
After our paper came out, an independent group published the NMR structure of p31-43 and its P36A and F37A mutants (3). This work presented apparently contrasting results based on NMR spectroscopy suggesting p31-43 Gliadin is mainly monomeric, but not discarding the presence of possible aggregated structures. As the peptide structures were deposited in the Protein Data Bank, we reanalyzed our molecular dynamics trajectory conducting a structural comparison between the conformations sampled in our simulations and those based on NMR. As it can be observed from figure 1A-C, the matching observed between monomer simulations and experimental structures is outstanding. Moreover, the structural superposition between individual peptides within the oligomer and the experimental structures is also remarkable (Figure 1D). This provides support to the idea that “the monomers are in fast exchange with self-assembled structures” and that “the 3D models represent the secondary elements adopted also in the oligomeric forms” (3). Indeed, selected conformations from the simulations are indistinguishable from those coming from the experimental determination (Figure 1D).
Besides highlighting the capacity of our simulation method to characterize the conformational behavior of peptides and the effect of single point mutations (Figure 1A-C), the remarkable agreement between simulations and experiment in the oligomeric case provides new evidence indicating that the p31-43 Gliadin peptide suffers minor conformational changes when passing from monomeric to oligomeric states. This further strengths the idea that oligomers might work as reservoirs that protect p31-43 from degradation. Though p31-43 monomers are quite resistant to degradation, the self-assembly process extends the persistence of large aggregates with higher toxic potency, particularly when disruption of normal physiology of internal vesicles (1) and release of danger signals are considered as driving events for inflammation and cell damage (4).

Caption to Figure
Figure 1. Structural superposition of the best matching solution between simulated monomers and NMR derived conformations. (A) wt p31-43, (B) P36A and (C) F37A mutants. (D) Comparison between simulated wt p31-43 conformers within the oligomer and NMR results. Right: the final structures obtained by molecular dynamics of each peptide forming the oligomer (Y-axis) are compared against all the conformers reported in the NMR family of structures (X-axis). The degree of structural similarity is reported as the root mean square deviation (RMSD) between the C-alpha carbons of simulated and NMR derived conformers. Small RMSD values (red-yellow) identify high structural similarity. Left: structural superposition on the right corresponds to the best matching peptides in the oligomer overlapped to a NMR structure.

Keywords: Coarse Grained (CG), Simulations, Celiac Disease, p31-43, gliadin peptides, Sirah Force Field

Received: 02 Jul 2019; Accepted: 04 Oct 2019.

Copyright: © 2019 Barrera, Chirdo and Pantano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Sergio Pantano, Institut Pasteur de Montevideo, Montevideo, 11400, Uruguay, spantano@pasteur.edu.uy