Hacking proteins with AI

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Oct 1, 2025

Discover how AI is revolutionizing protein design and vaccine development! The hosts delve into cutting-edge tools like AlphaFold and ProteinMPNN that help researchers engineer proteins for medicine. They discuss the potential of creating a Strep A vaccine and the significance of modifying antigens for better efficacy. With insights into small domain selection and the exciting prospects of designing entirely new proteins, this conversation highlights AI's role in accelerating preclinical research while underscoring the journey to clinical trials.

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INSIGHT

AI Lets Us Read And Reimagine Proteins

AI now predicts protein structures and enables design of proteins never seen in nature.
This unlocks medicines, improved vaccines, and new industrial applications.

ANECDOTE

Hands-On At The Institute For Protein Design

Jacob visited the Institute for Protein Design and used ProteinMPNN on a Strep A antigen called ScpA.
He tried redesigning it to be a smaller, better immunogen using newer AI tools.

INSIGHT

Natural Proteins Often Need Engineering

Natural proteins often need changes to be practical vaccines or medicines.
Requirements include solubility, manufacturability, stability, and safe immunogenicity.

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Nature didn’t evolve all the proteins we need, but maybe artificial intelligence can help. Jacob and Saloni explore how tools like AlphaFold and ProteinMPNN are helping researchers re-engineer proteins, to make them safer, more stable, and more effective. They talk about how new technologies could help make a long-sought vaccine against Strep A, which causes scarlet fever and rheumatic heart disease, and how similar tools have already led to breakthroughs against COVID and RSV.

Hard Drugs is a new podcast from Works in Progress and Open Philanthropy about medical innovation presented by Saloni Dattani and Jacob Trefethen.

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Courses:

EMBL-EBI. AlphaFold: A practical guide https://www.ebi.ac.uk/training/online/courses/alphafold/

Articles:

Monica Jain et al. (2022) Exosite binding modulates the specificity of the immunomodulatory enzyme ScpA, a C5a inactivating bacterial protease. https://pmc.ncbi.nlm.nih.gov/articles/PMC9464890/
Jakki Cooney et al. (2008) Crystal structure of C5a peptidase https://www.rcsb.org/structure/3EIF
Hui Li et al. (2017) Mutagenesis and immunological evaluation of group A streptococcal C5a peptidase as an antigen for vaccine development and as a carrier protein for glycoconjugate vaccine design https://pubs.rsc.org/en/content/articlelanding/2017/ra/c7ra07923k

Lectures:

Rosetta Commons (2024) AlphaFold – ML for protein structure prediction https://www.youtube.com/watch?v=SVrn8_8aKO8
Rosetta Commons (2024) MPNN – ML for protein sequence design https://www.youtube.com/watch?v=6z4XmUAwdNA

Acknowledgements:

Aria Babu, editor at Works in Progress
Graham Bessellieu, video editor
Rachel Shu, on-site editor
Anna Magpie, fact-checking
Abhishaike Mahajan, cover art
Atalanta Arden-Miller, art direction
David Hackett, composer

Works in Progress & Open Philanthropy

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