Development of Novel Binding Partners for the Identification and Quantification of Small Molecules: Differentiable protein design for small molecule binding

Dr James Murray and Prof Geoff Baldwin have been awarded a Defence Science and Technology Laboratory 4-year PhD to start in Oct 2024. This studentship includes stipend and tuition fees for UK students paid at the UKRI level.

Only students classified as Home (UK) for fees purposes are eligible to apply.

The project is to design protein-based small molecule binding partners, for the purposes of detection, identification and quantitation of small molecules. We will create de novo protein binders with computational protein design, using a diffusion deep-learning generative models, and then synthesise and test them. There has recently been a quantum leap in the capabilities of protein design, due to the development of deep-learning based tools, kick-started by the release of AlphaFold2 in 2021. An important application of protein design is to bind small molecules for detection. Such proteins have usually been raised as antibodies or produced by screening libraries, but these processes are unreliable and labour-intensive. Here we propose to put together an entirely differentiable pipeline, where the binding energy of the ligand is another parameter to be optimised in a deep-learning protein design pathway. The student will design ligand binding proteins, then express and purify them. We will then characterise the designs for binding to the target ligand, and then optimise the designs in an iterative process. Ligand binding will be tested via biochemical assays, including tryptophan based fluorescence and ELISAs.

Training will be gained in computational protein design, protein generative models, protein expression, purification and characterization. The project would suit a computationally oriented biochemist, or someone with a computational/physical science background and an interest in protein design.

Funding Notes and Eligibility:

This project is funded by DSTL. Funding includes payment of college fees and a tax-free stipend for four years starting from October 2024. Please note that the nature of the sponsor means that only UK nationals, UK dual nationals, EU nationals with settled status, or foreign nationals with indefinite leave to remain are eligible. You will have an appropriate undergraduate degree with a 2:1 result or better. Additionally, a Masters degree with Merit or better in a relevant topic will be preferred.

Informal enquires can be made to Dr James Murray (j.w.murray@imperial.ac.uk)

How to apply:

Please email Dr James Murray (j.w.murray@imperial.ac.uk) and include in your application:

• Personal Statement (max. 2 pages A4, Arial/Calibri font size 11)
• CV
• Please arrange for two academic reference letters to be sent directly to Dr James Murray

Full applications made before 30^th June 2024 will be considered at any time.