Designing Immunity from First Principles: AI Protein Design and Structural Biology to Build Synthetic Plant Immune Receptors. Fully Funded 4-Year

About the project

About the Project Build a plant immune receptor that has never existed in nature. This fully funded four-year Gatsby Sainsbury PhD at Durham combines generative AI protein design, structural biology and plant immunity. Plant pathogens evolve faster than we can find resistance genes to stop them. Plants defend themselves using intracellular immune receptors called NLRs, which detect pathogen virulence proteins (effectors) and trigger defence. The conventional route to new resistance is to search natural diversity for a receptor that happens to recognise the pathogen in question. That search is slow, and the receptors it yields are constrained by their evolutionary history. This project takes a different route. Rather than searching for receptors, you will design them, and rather than targeting effectors one at a time, you will target the structural folds that entire effector families share. The project has two connected halves. Mapping effector fold space. Pathogen effectors diverge so rapidly in sequence that families related by structure are invisible to conventional sequence searching. These sequence-unrelated but structurally similar (SUSS) families are a strategic target: a single binding surface conserved across a family offers recognition that is harder for the pathogen to escape. You will build and mine a structural reference set of pathogen effectors, using structure prediction and structural comparison across bacterial, fungal, oomycete and other plant pathogens, to identify conserved surfaces worth designing against. This is a computational and structural bioinformatics challenge with a clear experimental endpoint. Building the receptor. Using generative design tools including RFdiffusion, ProteinMPNN and BindCraft, you will design de novo protein modules that bind those conserved surfaces. The harder and more interesting problem is what to put them into. Current engineering grafts new recognition modules into natural NLR scaffolds, which are poorly behaved biochemically and often produce receptors that are either dead or constitutively active. You will instead design synthetic receptor architectures from scratch: new-to-nature sequences that adopt the domain organisation of natural immune receptors but are built for tractability, allowing structural and biophysical characterisation that natural NLRs have resisted for decades. Designs will be expressed, purified and characterised structurally by X-ray crystallography and cryo-EM, and tested functionally in planta. Working with Marc Knight, you will establish whether designed receptors signal authentically. Natural immune activation produces characteristic cytosolic calcium signatures that are decoded into defence gene expression. Using bioluminescent calcium reporters and quantitative gene expression analysis, you will ask whether synthetic receptors reproduce genuine immune signalling or merely trigger cell death, a distinction that determines whether designed resistance is useful in a crop. The project is genuinely two-sided, and you do not need to arrive fluent in both. Applicants from computational, physical and biological backgrounds are equally welcome: computational biology, bioinformatics, machine learning, biophysics, structural biology, biochemistry and plant science are all strong starting points. What matters is a strong foundation in one and real appetite to develop in the others. Supervision and environment You will join the Bentham Lab in the Department of Biosciences and the Centre for Programmable Biological Matter (CPBM) at Durham, a Leverhulme Trust-funded hub for engineering programmable biological systems, with co-supervision from Marc Knight. The lab works at the intersection of structural biology, computational protein design and plant immunity, and is part of a collaborative network spanning Durham, the John Innes Centre, The Sainsbury Laboratory and the University of Washington. Durham provides genomics, bioimaging, mass spectrometry and controlled plant growth facilities. The lab shares space with two further CPBM groups, givingday-to-day access to a wide range of expertise. Learn more about the lab at https://benthamlab.org The project builds on established results: the Bentham Lab has shown that generative design tools can build de novo sensory domains conferring specific effector recognition when integrated into a plant NLR chassis, and that binding and signal relay are separable problems. This studentship addresses what comes next. Training You will be trained in generative protein design and structure prediction, structural bioinformatics at proteome scale, recombinant protein expression and purification, X-ray crystallography and cryo-EM, biophysical characterisation, plant transient expression and quantitative calcium and gene expression assays. Alongside this, Gatsby students take part in the annual Easter training weekend in Cambridge, where students are mentored in giving talks, producing posters and writing papers, and join the Gatsby Plant Science Network. Gatsby students are also expected to spend six months of their third or fourth year at another university or institute, with additional funding provided towards the costs, an opportunity to build an independent network beyond Durham. How to apply Informal enquiries are warmly encouraged and are the best way to find out whether the project suits you. To apply, please email Adam Bentham at adam.r.bentham@durham.ac.uk by Friday 27 November 2026, attaching a CV, a covering letter of no more than one page explaining your interest in the project and what you would bring to it, and a transcript of your results to date. Applications come directly to the supervisor, who selects one candidate to put forward to the Gatsby panel. The selected candidate then writes a short research proposal, with the supervisor's input, ahead of the January interview. We are committed to an inclusive and supportive research environment, welcome applications from all backgrounds, and are happy to discuss flexible arrangements and any support you may need.

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