Decoding CDR Dynamics to Engineer High Affinity Antibodies for Next Generation Therapeutics

About the Project

Project Summary

This project will investigate how complementarity‑determining region (CDR) structural dynamics guide affinity maturation in antibodies, with the goal of improving their use in global health and biotechnology.

Project

Antibodies and nanobodies have emerged as versatile therapeutic and diagnostic tools due to their size, stability, and ability to access epitopes that conventional antibodies cannot. However, their binding performance depends critically on the structural plasticity of their complementarity‑determining regions (CDRs), especially CDR3. During affinity maturation, subtle shifts in loop conformation, flexibility, and packing can dramatically enhance antigen recognition, yet the fundamental rules governing these dynamic changes remain poorly understood. This knowledge gap limits our ability to rationally engineer high‑affinity VHHs for real‑world impact, including infectious disease diagnostics, cancer therapeutics, and environmental biosensing.

This PhD project aims to decode how CDR dynamics shape the evolutionary trajectory of VHH affinity maturation. You will integrate structural biology, molecular modelling, and experimental validation to map how conformational ensembles shift as VHHs evolve from germline‑like to high‑affinity states. Using curated libraries of experimentally evolved VHH variants, you will employ molecular dynamics simulations and machine‑learning‑based structural analysis to identify dynamic motifs that correlate with improved binding. These predictions will be tested through expression, biophysical characterisation, and affinity measurements of selected nanobody variants.

By linking loop flexibility to functional maturation, this project will establish predictive principles for engineering next‑generation antibody therapeutics. Beyond scientific discovery, the project carries strong real‑world relevance: VHHs are rapidly becoming frontline tools in tackling antimicrobial resistance, developing low‑cost diagnostics for underserved communities, and creating more sustainable biotech pathways. As a doctoral researcher, you will contribute to technologies that can genuinely improve global health outcomes.

This interdisciplinary project is ideal for motivated students interested in structural biology, computational modelling, and antibody engineering. Training will be provided to support your development. What matters most is curiosity, enthusiasm, and a desire to use science to make a positive difference.

Training Opportunities

You will receive comprehensive training in structural biology techniques, structural modelling, protein engineering, and biophysical assay design. Laboratory training will include recombinant protein expression, purification, protein crystallography, NMR, and affinity measurements (e.g., SPR/BLI). Professional development opportunities include presenting at conferences, contributing to publications, collaborating with interdisciplinary research teams, and engaging with industry partners working in antibody design. By the end of the PhD, you will be equipped with a highly competitive skillset spanning both wet‑lab and computational structural biology.

Outputs

Expected outputs include: (1) a comprehensive structural–dynamic map of VHH affinity maturation; (2) predictive models linking CDR flexibility to binding performance; (3) engineered nanobody variants with optimised affinity and stability; and (4) at least two peer‑reviewed publications. Additional outputs may include conference presentations, and collaboration with industry partners to translate findings into therapeutic or diagnostic applications.

Apply at:

https://le.ac.uk/study/research-degrees/research-subjects/molecular-and-cell-biology

PhD entry requirements:https://le.ac.uk/study/research-degrees/entry-reqs

Supervisor contact details:

Dr Gareth Hall - gh126@leicester.ac.uk

Dr Fred Muskett - fwm1@leicester.ac.uk

References

1. Muyldermans S. Nanobodies: natural single domain antibodies. Annu Rev Biochem. 2013.
2. Fernandez Quintero ML et al. Structural dynamics of CDR loops control antibody binding specificity. Front Immunol. 2020.
3. Steeland S, Vandenbroucke RE, Libert C. Nanobodies as therapeutics: big opportunities for small antibodies. Drug Discov Today. 2016.