[lysozyme]

For those like myself who design proteins for a living, the open secret is that well before AlphaFold, it was pretty much possible to get a good-enough structure of any particular protein you really cared about (from say 2005) by other means, namely Baker’s Rosetta.

I constantly use AlphaFold structures today [1]. And AlphaFold is fantastic. But it only replaces one small step in solving any real-world problem involving proteins such as designing a safe, therapeutic protein binder to interrupt cancer-associated protein-protein interactions or designing an enzyme to degrade PFAS.

I think the primary achievement is that it gets protein structures in front of a lot more smart eyes, and for a lot more proteins. For “everyone else” who never needed to master computational protein structure prediction workflows before, they now have easy access to the rich, function-determinative structural information they need to understand and solve their problem.

The real tough problem in protein design is how to use these structure predictions to understand and ultimately create proteins we care about.

1. https://alexcarlin.bearblog.dev/multistate-protein-design-wi...

[throwawaymaths]

Forget Rosetta. Even installing that shit was hard, and running it on a sufficiently beefy machine was probably really not a thing in the late aughts. For protein design you mostly just need a quick and dirty estimate of what it looks like, and you have friend proteins that can be used to homology map, you could just use phyre/phyre2, which is an online threading model and be close enough to get work done. Upload the pdb, upload the sequence, bing bam boom.

[hackernewds]

Rosetta was clunky and not even David Baker would endorse it

[moralestapia]

Citation needed.

I worked on protein structure prediction for a couple years and it was sota.