Flower Darren R, McSparron Helen, Blythe Martin J, Zygouri Christianna, Taylor Debra, Guan Pingping, Wan Shouzhan, Coveney Peter V, Walshe Valerie, Borrow Persephone, Doytchinova Irini A
Edward Jenner Institute for Vaccine Research, High Street, Compton, Berkshire, RG0 7NN, UK.
Novartis Found Symp. 2003;254:102-20; discussion 120-5, 216-22, 250-2.
The immune system is hierarchical and has many levels, exhibiting much emergent behaviour. However, at its heart are molecular recognition events that are indistinguishable from other types of biomacromolecular interaction. These can be addressed well by quantitative experimental and theoretical biophysical techniques, and particularly by methods from drug design. We review here our approach to computational immunovaccinology. In particular, we describe the JenPep database and two new techniques for T cell epitope prediction. One is based on quantitative structure-activity relationships (a 3D-QSAR method based on CoMSIA and another 2D method based on the Free-Wilson approach) and the other on atomistic molecular dynamic simulations using high performance computing. JenPep (http://www.jenner.ar.uk/ JenPep) is a relational database system supporting quantitative data on peptide binding to major histocompatibility complexes, TAP transporters, TCR-pMHC complexes, and an annotated list of B cell and T cell epitopes. Our 2D-QSAR method factors the contribution to peptide binding from individual amino acids as well as 1-2 and 1-3 residue interactions. In the 3D-QSAR approach, the influence of five physicochemical properties (volume, electrostatic potential, hydrophobicity, hydrogen-bond donor and acceptor abilities) on peptide affinity were considered. Both methods are exemplified through their application to the well-studied problem of peptide binding to the human class I MHC molecule HLA-A*0201.
免疫系统具有层次性，包含多个层次，展现出许多涌现行为。然而，其核心是分子识别事件，这些事件与其他类型的生物大分子相互作用并无二致。定量实验和理论生物物理技术，特别是药物设计方法，能够很好地解决这些问题。在此，我们回顾我们在计算免疫疫苗学方面的方法。特别是，我们描述了JenPep数据库以及两种预测T细胞表位的新技术。一种基于定量构效关系（一种基于比较分子相似性指数分析的3D-QSAR方法和另一种基于Free-Wilson方法的2D方法），另一种基于使用高性能计算的原子分子动力学模拟。JenPep（http://www.jenner.ar.uk/ JenPep）是一个关系数据库系统，支持有关肽与主要组织相容性复合体、TAP转运蛋白、TCR-pMHC复合体结合的定量数据，以及B细胞和T细胞表位的注释列表。我们的2D-QSAR方法考虑了单个氨基酸以及1-2和1-3残基相互作用对肽结合作用的贡献。在3D-QSAR方法中，考虑了五种物理化学性质（体积、静电势、疏水性、氢键供体和受体能力）对肽亲和力的影响。这两种方法都通过应用于肽与人I类MHC分子HLA-A*0201结合这一研究充分的问题进行了例证。
