Exploring the conformational landscape of the 33-mer peptide: a computational approach

AMUNDARAIN MARÍA JULIA; VIETRI AGUSTÍN; DODERO VERÓNICA ISABEL; COSTABEL MARCELO DANIEL

São Paulo

Congreso; 20th International Congress of the International Union for Pure Applied Biophysics (IUPAB); 2021

International Union for Pure Applied Biophysics (IUPAB)

Introduction and objectives: The 33-mer peptide is a digestion product of thegluten α2-gliadin protein. This proline- and glutamine-rich peptide is a putativetrigger of the immune response in coeliac disease patients after gluten ingestion.In addition, in the small intestine, 33-mer is deamidated in three glutamines,which allows its recognition by the immune system, initiating the inflammationprocess. There is experimental evidence that both peptides (the WT and thedeamidated peptide) form aggregates in physiologically relevant conditions, andit has been hypothesized that their oligomerization might be involved in thedevelopment of the disease. However, an accurate and complete structuraldescription of the peptide and the initial oligomers has remained elusive.This work aims to explore computationally the conformational space of both the33-mer peptide and its deamidated form as a first step to understand theiraggregation properties and their influence on gluten-related diseases.Materials and methods: The methods and force fields to assess IntrinsicallyDisordered Peptides? (IDPs) structures have evolved fast-paced in the last years.We performed classical molecular dynamics (MD) simulations withGROMACS2020 using the atomistic AMBER03WS force field (1.5 μs eachpeptide) and the coarse-grained SIRAH force field (30 μs per peptide), whichhave been successfully employed to study other IDPs. The starting structures forboth simulations were elongated peptides obtained from an experimentally basedmodelling scheme.Results and conclusions: From atomistic unbiased MD simulations, we obtainedmainly a wide range of elongated structures. However, through the coarsegrained approach, we were able to assess possible folded and unfolded states.In both representations, the WT peptide visited more compact states than thedeamidated one. The representative structures of both types of simulationsshowed good agreement with the experimental data available. Both the 33-merpeptide and its deamidated form presented several stable structuralarrangements, which should be considered to assess the aggregation process.