Ochoa Rodrigo, Cardim-Pires Thyago R, Sant'Anna Ricardo, Cossio Pilar, Foguel Debora
Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, 050010 Medellin, Colombia.
Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach/Riss, Germany.
Comput Struct Biotechnol J. 2023 Feb 18;21:1746-1758. doi: 10.1016/j.csbj.2023.02.031. eCollection 2023.
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 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 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.
那些也能够结合主要组织相容性复合体（MHC）等位基因的表位的聚集，引发了关于表位聚集体形成与其对MHC受体亲和力之间潜在联系的问题。我们首先对一个MHC II类表位的公共数据集进行了全面的生物信息学评估，发现较高的实验结合与较高的聚集倾向预测值相关。然后我们聚焦于P10这个例子，它是一种用于对抗[此处原文缺失相关疾病名称]的候选疫苗表位，会聚集形成淀粉样原纤维。我们使用一种计算方案来设计P10表位的变体，以研究其对人类MHC II类等位基因的结合稳定性与其聚集倾向之间的联系。对设计出的变体的结合进行了实验测试，以及它们的聚集能力。高亲和力的MHC II类结合物更倾向于聚集形成能够结合硫黄素T和刚果红的淀粉样原纤维，而低亲和力的MHC II类结合物则保持可溶状态或形成罕见的无定形聚集体。这项研究表明了表位的聚集倾向与其对MHC II类裂隙的亲和力之间可能存在的联系。
