Protein complex prediction with AlphaFold-Multimer

If the monomer is completely unstable by itself, and wouldn't fold, I'm pretty sure 5 of them are not going to fold simultaneously into a multimer. So it would be a good guess that the monomers are going to fold first into something that at least looks roughly like the final product and then assemble and change configuration.

But no I haven't read any articles studying this in detail. I do recall seeing studies on the evolution of oligomers, where the monomer exists by itself but evolves to polymerize at the expense of its monomeric stability.

One of the main comparisons in the paper is to ClusPro docking of Alphafold-generated monomers. ClusPro uses FFT-based sampling of rotations and translations of rigid monomers followed by minimization to allow the monomers to relax and adapt. This paper allows significantly more adaptation in the formation of multimers than ClusPro does.

Historically, most multimer prediction software has required well structured subunits. And the field was largely built around benchmarks that had structures of subunits [0]. Over the last decade, there has been a increased recognition that many heterodimers are made up of a well structured protein and an intrinsically disordered protein [1] (or intrinsically disordered region of another protein). This lead to a lot of efforts to predict what residues are in the interface and then generating ensembles of "peptide" structures (where peptide is <~15 residues) to model the predicted interface without having to predict larger structure.

So, to answer, the structures of the original protein change. An increasingly important area is proteins that don't have much structure as a monomer, but you'll see changes in ones that have well-structured monomers as well. If you dig into some of the difficult cases of the zlab benchmark (using pymol for example), you'll find that in many of those cases, the proteins undergo large conformational changes in forming the complex.

[0] https://zlab.umassmed.edu/benchmark/

[1] https://en.wikipedia.org/wiki/Intrinsically_disordered_prote...

So the simple possibility is rigid docking to get a surface between proteins. As with everything in biology, things can be more complicated.

For example, from here :

https://elifesciences.org/articles/22889

it starts with:

>Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners

In other words, binding of a protein to another can change its shape (conformation).

Its amazing having a company with the technology & innovation focus such as Google funding, pushing, and publishing AI research.

Everyone wins, and will continue to do so until the research labs at Google, Facebook, Apple etc... abandon their openness culture -- which I don't see happening anytime soon mostly because of the attitudes and culture of openness of the engineers & researches at said labs.

Great times we live in...

Google's text-to-speech and speech-to-text models are still closed source ...

Makes me wonder how much DeepMind could make just by keeping their protein folding proprietary and charging per use.