PDF(Pubmed)
Abstract：
Deeper understanding of T-cell-mediated adaptive immune responses is important for the design of cancer immunotherapies and antiviral vaccines against pandemic outbreaks. T-cells are activated when they recognize foreign peptides that are presented on the cell surface by Major Histocompatibility Complexes (MHC), forming peptide:MHC (pMHC) complexes. 3D structures of pMHC complexes provide fundamental insight into T-cell recognition mechanism and aids immunotherapy design. High MHC and peptide diversities necessitate efficient computational modelling to enable whole proteome structural analysis. We developed PANDORA, a generic modelling pipeline for pMHC class I and II (pMHC-I and pMHC-II), and present its performance on pMHC-I here. Given a query, PANDORA searches for structural templates in its extensive database and then applies anchor restraints to the modelling process. This restrained energy minimization ensures one of the fastest pMHC modelling pipelines so far. On a set of 835 pMHC-I complexes over 78 MHC types, PANDORA generated models with a median RMSD of 0.70 Å and achieved a 93% success rate in top 10 models. PANDORA performs competitively with three pMHC-I modelling state-of-the-art approaches and outperforms AlphaFold2 in terms of accuracy while being superior to it in speed. PANDORA is a modularized and user-configurable python package with easy installation. We envision PANDORA to fuel deep learning algorithms with large-scale high-quality 3D models to tackle long-standing immunology challenges.
摘要：
加深对T细胞介导的适应性免疫反应的理解对于设计针对大流行爆发的癌症免疫疗法和抗病毒疫苗很重要。当T细胞识别通过主要组织相容性复合物（MHC）在细胞表面呈递的外源肽时，T细胞被激活。形成肽:MHC(pMHC)复合物。pMHC复合物的3D结构提供了对T细胞识别机制的基本见解，并有助于免疫疗法设计。高MHC和肽多样性需要有效的计算建模以实现整个蛋白质组结构分析。我们开发了PANDORA,pMHCI类和II类（pMHC-I和pMHC-II）的通用建模管道，并在这里展示其在pMHC-I上的表现。给定一个查询，PANDORA在其广泛的数据库中搜索结构模板，然后将锚固约束应用于建模过程。这种受限的能量最小化确保了迄今为止最快的pMHC建模管道之一。在一组超过78种MHC类型的835种pMHC-I复合物上，PANDORA生成的模型的平均RMSD为0.70µ，在前10个模型中的成功率为93％。PANDORA与三种最先进的pMHC-I建模方法具有竞争力，在准确性方面优于AlphaFold2，同时在速度上优于AlphaFold2。PANDORA是一个模块化和用户可配置的python包，易于安装。我们设想PANDORA将为深度学习算法提供大规模高质量3D模型，以应对长期存在的免疫学挑战。
