This is a CASE studentship, in collaboration with Immunocore (www.immunocore.com), which will include a placement at the company (in Abingdon).
Most biomolecular interactions are thought to increase the (local) rigidity of a complex and this is often exploited when designing new (small-molecule) drugs. However, for biopharmaceuticals, tuning the dynamics and flexibility of interactions is potentially a pathway to potent and specific ’biologic’ drugs. Using affinity-matured designed CD8+ T-cell receptors (TCRs), bi-specific biologics can designed to target a range of diseases, including cancer. A better understanding of the molecular determinants that govern CD8+ T-cell mediated immunity is key to improve the activity and specificity novel therapeutic interventions that can enhance (immunotherapy, vaccines, etc). This builds on the interaction of TCRs with the human leukocyte antigen bound to a peptide (pHLA). To achieve the desired T cell activation, both affinity and specificity of TCR-pHLA binding should be finely tuned; very strong TCR-pHLA affinities can result in reduced potency, and lack of specificity will lead to cross-reaction (and thus side-effects).
The project will focus on understanding and predicting the binding between TCR, peptide and HLA, including the role that the peptide plays in TCR recognition, which is important in determining the functional outcome of an immune response. Our recent work (in review) indicates that the recognition peptide is able to modulate the conformational dynamics of the HLA and that these changes are detected by the TCR, resulting in substantial changes in TCR-peptide-HLA binding affinity. Developing new biopharmaceuticals incorporating information on detailed molecular dynamics is a new approach for the design of peptide-based drugs and opens up new opportunities for therapeutics.
Detailed biomolecular simulation (atomistic molecular dynamics) is ideally placed to explore and predict the potential of new peptide-based drugs. In particular, the use of enhanced sampling allows the exploration of very large effective time-scales key to accurately capturing the molecular dynamics of TCR-peptide-HLA binding and binding-free energy calculations can now, in principle, accurately predict affinities for complex systems. Using these approaches, combined with complementary experimental tools and comparison with extensive (structural and affinity) in-house data from the industrial partner Immunocore, the project will develop the ability to rationally design peptide-based drugs for T cell activation.
The project is truly cross-disciplinary, incorporating new advances in computational simulation, novel experimental techniques to complement the computational work, and the direct involvement of an ideal industrial partner. The student will be embedded in the Bristol Computational Biochemistry group (www.bristol.ac.uk/bcompb) and the Bristol BioDesign institute, ensuring fruitful interactions with other computational biochemists and experts in biomolecular design, relevant seminar programmes, as well as ample computational resources. Notably, the student will further have the advantage of spending time in different research environments (Bristol, Bath and with the industrial partner, Immunocore). The training potential for the student is outstanding and will enable the successful student to acquire a range of skills that will arm them for a future career in academic or industrial bioscience, which would allow them to build a career in the growing (computational) biopharmaceutical area.
Main supervisor: Dr Marc van der Kamp (Biochemistry, University of Bristol)