The art of protein design with AI

What if you could design a protein never seen in nature? In this episode of Hard Drugs, and explore how researchers are using new tools like RFDiffusion, AlphaFold, and ProteinMPNN to ‘hallucinate’ entirely novel proteins: designing them from scratch to solve problems evolution hasn’t tackled. They talk about how these technologies could transform medicine, agriculture, and materials science. Along the way, they reflect on the surprising ways AI is changing the process of science itself.

01:12 Why build proteins nature never made?
06:33 Designing a hepatitis B-blocking protein from scratch
12:47 Hallucinating new proteins with diffusion models
18:20 AlphaFold changes everything
28:10 How AI models design and test proteins
32:33 What AI still can’t predict about proteins
40:45 From computer-made proteins to real-world drugs
44:33 Protein Lego: building shapes, tubes, and scaffolds
49:45 The future of AI protein design

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

You can watch or listen on YouTube, Spotify, or Apple Podcasts.

Saloni’s substack newsletter: https://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:

• Tanja Kortemme (2024) De novo protein design—From new structures to programmable functions https://www.cell.com/cell/fulltext/S0092-8674(23)01402-2

• Jie Zhu et al. (2021) Protein Assembly by Design https://pubs.acs.org/doi/10.1021/acs.chemrev.1c00308

Lectures:

• Rosetta Commons (2024) Diffusion models for protein structure generation (and design) https://www.youtube.com/watch?v=OEnY2yA3jy8

• 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

Transcript

Jacob Trefethen:

I think the starting gun is basically 2022. What we’re gonna see, I believe, if people put the effort in is a lot of structural biologists who know how to use these computational tools, matching up with experts in particular fields who know a lot about diagnostics, or who know a lot about the heart, or who know a lot about a given infectious disease, or know a lot about a given agricultural problem, and in combination, I think those teams of people are gonna do really incredible things.

Saloni Dattani:

Alright. Well, we’ve talked about proteins, all the cool stuff proteins can do. We’ve talked about the history of insulin, one ...