5 ms·
As an example, the majority of current drug targets are membrane proteins, of which most are multimers, which makes stuff like this a key part of predicting imp
by l33tman 5y ago
As an example, the majority of current drug targets are membrane proteins, of which most are multimers, which makes stuff like this a key part of predicting important protein complexes. Membrane proteins are also notoriously difficult to get structures of which makes it even more interesting.
BTW, I'm not sure how well AlphaFold predicts structures that are part of multimers in the first place? But since they have to be (relatively) stable as a monomer before locking in place, I guess they can be predicted without considering their final part of a complex. Still, feels like some kind of symbiosis between this and the structure prediction itself could exist.
- cowsandmilk 5y ago> since they have to be (relatively) stable as a monomer before locking in place What is your basis for this claim?
- l33tman 5y agoIf 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.
- andy_ppp 5y agoDoes the actual structure of the original protein change to "fit" into the multimer or is it just the protein is fixed and the orientation/tessellation is what is being calculated? Or Both?
- cowsandmilk 5y agoOne 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/ https://zlab.umassmed.edu/benchmark/ [1] https://en.wikipedia.org/wiki/Intrinsically_disordered_proteins https://en.wikipedia.org/wiki/Intrinsically_disordered_prote...
- gilleain 5y agoSo 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 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).