IDP Force Fields Applied to Model PPII-Rich 33-mer Gliadin Peptides

The
33-mer gliadin peptide and its deamidated metabolite, 33-mer
DGP, are the immunodominant peptides responsible for the adaptive
immune response in celiac disease (CD). CD is a complex autoimmune
chronic disorder triggered by gluten ingestion that affects the small
intestine and affects ∼1% of the global population. The 33-mers
are polyproline II-rich (PPII) and intrinsically disordered peptides
(IDPs), whose structures remain elusive. We sampled the conformational
ensembles of both 33-mer peptides via molecular dynamics simulations
employing two force fields (FFs) (Amber ff03ws and Amber ff99SB-disp) specifically validated for other IDPs.
Our results show that both FFs allow the extensive exploration of
the conformational landscape, which was not possible with the standard
FF GROMOS53A6 reported before. Clustering analysis
of the trajectories showed that the five largest clusters (78–88%
of the total structures) present elongated, semielongated, and curved
conformations in both FFs. Large average radius of gyration and solvent-exposed
surfaces characterized these structures. While the structures sampled
are similar, the Amber ff99SB-disp trajectories explored
folded conformations with a higher probability. In addition, PPII
secondary structure was preserved throughout the trajectories (58–73%)
together with a non-negligible content of β structures (11–23%),
in agreement with previous experimental results. This work represents
the initial step in studying further the interaction of these peptides
with other biologically relevant molecules, which could lead to finally
disclose the molecular events that lead to CD.