Developing better biopharmaceuticals using biomolecular simulation and design

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.