Connection between MHC class II binding and aggregation propensity: The antigenic peptide 10 of Paracoccidioides brasiliensis as a benchmark study

Rodrigo Ochoa; Thyago R Cardim-Pires; Ricardo Sant'Anna; Pilar Cossio; Debora Foguel

doi:10.1016/j.csbj.2023.02.031

Connection between MHC class II binding and aggregation propensity: The antigenic peptide 10 of Paracoccidioides brasiliensis as a benchmark study

Comput Struct Biotechnol J. 2023 Feb 18:21:1746-1758. doi: 10.1016/j.csbj.2023.02.031. eCollection 2023.

Authors

Rodrigo Ochoa^{1

2}, Thyago R Cardim-Pires³, Ricardo Sant'Anna³, Pilar Cossio^{1

4

5}, Debora Foguel³

Affiliations

¹ Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, 050010 Medellin, Colombia.
² Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach/Riss, Germany.
³ Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
⁴ Center for Computational Mathematics, Flatiron Institute, New York, NY, United States.
⁵ Center for Computational Biology, Flatiron Institute, New York, NY, United States.

Abstract

The aggregation of epitopes that are also able to bind major histocompatibility complex (MHC) alleles raises questions around the potential connection between the formation of epitope aggregates and their affinities to MHC receptors. We first performed a general bioinformatic assessment over a public dataset of MHC class II epitopes, finding that higher experimental binding correlates with higher aggregation-propensity predictors. We then focused on the case of P10, an epitope used as a vaccine candidate against Paracoccidioides brasiliensis that aggregates into amyloid fibrils. We used a computational protocol to design variants of the P10 epitope to study the connection between the binding stabilities towards human MHC class II alleles and their aggregation propensities. The binding of the designed variants was tested experimentally, as well as their aggregation capacity. High-affinity MHC class II binders in vitro were more disposed to aggregate forming amyloid fibrils capable of binding Thioflavin T and congo red, while low affinity MHC class II binders remained soluble or formed rare amorphous aggregates. This study shows a possible connection between the aggregation propensity of an epitope and its affinity for the MHC class II cleft.

Keywords: Aggregation propensity; Amyloid fibril; Binding; MHC class II; Molecular Dynamics; Paracoccidioides brasiliensis; Peptide Design.