3.8 Article

pH-dependent structural diversity of profilin allergens determines thermal stability

Journal

FRONTIERS IN ALLERGY
Volume 3, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/falgy.2022.1007000

Keywords

allergens; profilins; protonation dependence; flexibility; thermal stability

Categories

Funding

  1. This work was supported by the Austrian Science Fund (FWF) via the grants P30737 and P30402, P34518 as well as DOC 30. [P30402, P34518]
  2. Austrian Science Fund (FWF)
  3. [P30737]

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The profilin allergen family is a class of proteins that are found in plants, viruses, and various eukaryotes. They have a conserved structural fold but exhibit differences in their biophysical properties. In this study, molecular dynamics simulations were performed to investigate the functional differences of three profilin allergens. It was found that these differences are related to conformational flexibility and thermal stability, emphasizing the importance of flexibility in understanding the biophysical differences between structurally similar allergens.
The family of profilin allergens is a common class of proteins found in plants, viruses and various eukaryotes including mammals. Profilins are characterized by an evolutionary conserved structural fold, which is responsible for their cross-reactive nature of Immunoglobulin E (IgE) antibodies. Despite their high overall structural similarity, they exhibit substantial differences in their biophysical properties, such as thermal and pH stability. To understand the origin of these functional differences of Amb a 8, Art v 4 and Bet v 2, we performed constant pH molecular dynamics simulation in combination with Gaussian accelerated MD simulations. Depending on the respective protonation at different pH levels, we find distinct differences in conformational flexibility, which are consistent with experimentally determined melting temperatures. These variations in flexibility are accompanied by ensemble shifts in the conformational landscape and quantified and localized by residue-wise B-factors and dihedral entropies. These findings strengthen the link between flexibility of profilin allergens and their thermal stability. Thus, our results clearly show the importance of considering protonation dependent conformational ensembles in solution to elucidate biophysical differences between these structurally similar allergens.

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