Developing better biopharmaceuticals using biomolecular simulation and design

细胞表面表达的T细胞受体（TCR）和肽-人白细胞抗原（pHLA）I类分子之间的相互作用使得T细胞（一种重要类型的白色血细胞）能够启动对异常细胞的直接杀伤。确定TCR-pHLA结合、亲和力和特异性的基础原则将有助于揭示T细胞抗原识别的性质，这对临床翻译具有重要意义。我们最近的模拟和实验结果发现：1）识别肽调节HLA的构象动力学，其由TCR检测，影响结合亲和力; 2）实现特异性需要优化广泛的TCR-pHLA界面上的接触; 3）模拟和分析可以正确地对低亲和力与高亲和力TCR-pHLA组合进行排名。这项工作表明，在设计能够有效激活T细胞的生物制剂时，不仅要考虑pHLA和TCR的结合界面，还要考虑其更广泛的分子灵活性。（结构，亲和力和交叉反应数据）与原子分子动力学模拟和随后的分析，以获得详细的了解TCR的动力学-pHLA相互作用及其与亲和力和特异性的关系。理解这种关系将有助于合理设计新的TCR变体，以调节TCR-pHLA相互作用的亲和力和特异性。我们将探索计算机模拟方法来预测特定pHLA靶点的TCR变体，并在Immunocore科学家进行实验测试之前，使用分子动力学工作流程对有希望的命中进行初步验证。这将说明基于模拟的方法用于识别新的候选生物药物的潜力，这是众所周知的挑战。通过利用Immunocore提供的大型高质量结构数据库，计算工作将成为可能。该项目福尔斯EPSRC的几个研究领域：“计算与理论化学”，“化学生物学与生物化学”和“生物物理学与软物质物理学”，因为它将开发用于设计生物活性分子的计算工具和技术（与布里斯托生物设计研究所的活动一致），使用计算化学方法来理解TCR-pHLA相互作用的生物物理学并将其输入TCR开发。通过更有效地开发基于TCR的治疗性分子，该项目福尔斯“开发未来疗法”的重大挑战（医疗保健技术主题），并可能导致治疗疾病的新疗法。

The interaction between the cell surface expressed T cell receptor (TCR) and peptide-human leukocyte antigen (pHLA) class I molecules enables T cells (an important type of white blood cell) to initiate direct killing of aberrant cells. Identifying the principles that underpin TCR-pHLA binding, affinity and specificity will help to reveal the nature of T cell antigen recognition with important implications for clinical translation. Our recent results from simulation and experiment have found that 1) the recognition peptide modulates the conformational dynamics of the HLA, which is detected by the TCR, affecting binding affinity; 2) achieving specificity requires optimising contacts across the broad TCR-pHLA interface; 3) simulation and analysis can correctly rank low versus high affinity TCR-pHLA combinations. The work suggests that not only the binding interface but also the wider molecular flexibility of pHLA and TCR should be considered for designing biologics that enable potent T cell activation.The proposed project builds on our current findings and will combine existing experimental information from our industrial collaborator, Immunocore (structures, affinities and cross-reaction data) with atomistic molecular dynamics simulations and subsequent analysis to obtain detailed insights in the dynamics of the TCR-pHLA interaction and its relation to affinity and specificity. Understanding this relationship will then aid the rational design of new TCR variants to tune the affinity and specificity of the TCR-pHLA interaction. We will explore in silico approaches to predict such TCR variants for specific pHLA targets, and use a molecular dynamics workflow for initial verification of promising hits, prior to experimental testing conducted by Immunocore scientists. This will illustrate the potential of a simulation-based approach for identifying new candidate biopharmaceuticals, which is notoriously challenging. The computational work will be made possible by exploiting the large library of high-quality structural data available at Immunocore.This project falls within several EPSRC research areas: 'Computational & Theoretical Chemistry', 'Chemical Biology and Biological Chemistry' and 'Biophysics and Soft Matter Physics', as it will develop computational tools and technologies for the design of biologically active molecules (well-aligned with activities in the Bristol BioDesign Institute), using computational chemistry approaches to understand the biophysics of TCR-pHLA interactions and feed this into TCR development. By enabling more efficient development of therapeutic TCR-based molecules, the project falls within the "Developing Future Therapies" Grand Challenge (Healthcare Technologies theme), and may lead to novel therapies to treat disease.