Developing better biopharmaceuticals using biomolecular simulation and design

利用生物分子模拟和设计开发更好的生物制药

• 批准号: 2446189
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2446189
• 关键词: Developing; better; biopharmaceuticals; using; biomolecular

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.

细胞表面表达的T细胞受体(TCR)与多肽-人类白细胞抗原(Phla)I类分子之间的相互作用使T细胞(一种重要的白细胞)能够启动对异常细胞的直接杀伤。确定支持TCR-Phla结合、亲和力和特异性的原理将有助于揭示T细胞抗原识别的本质，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TCR检测到的HLA的构象动力学，影响结合亲和力；2)要实现特异性，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和高亲和力的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，不仅应该考虑Phla和TCR的结合界面，而且应该考虑更广泛的分子灵活性。拟议的项目建立在我们目前的发现基础上，并将结合我们的工业合作伙伴免疫核心的现有实验信息(结构、亲和力和交叉反应数据)与原子分子动力学模拟和后续分析，以获得TCR-Phla相互作用的动力学及其与亲和力和特异性的关系的详细见解。了解这种关系将有助于合理设计新的TCR变体，以调整TCR-Phla相互作用的亲和力和特异性。我们将探索在计算机方法中预测特定Phla靶标的TCR变体，并使用分子动力学工作流在免疫核心科学家进行实验测试之前对有希望的HITS进行初步验证。这将说明基于模拟的方法在识别新的候选生物制药方面的潜力，这是出了名的具有挑战性。这个项目属于EPSRC的几个研究领域：“计算和理论化学”、“化学生物学和生物化学”以及“生物物理和软物质物理”，因为它将开发用于设计生物活性分子的计算工具和技术(与布里斯托尔生物设计研究所的活动很好地结合)，使用计算化学的方法来了解TCR-Phla相互作用的生物物理，并将其提供给TCR的开发。通过更有效地开发基于治疗性TCR的分子，该项目属于“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。