3 ms·

Does 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

Does 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 ago
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/ https://zlab.umassmed.edu/benchmark/ [1] https://en.wikipedia.org/wiki/Intrinsically_disordered_proteins https://en.wikipedia.org/wiki/Intrinsically_disordered_prote...
gilleain 5y ago
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 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).
- andy_ppp 5y ago
  It really does seem so incredibly unlikely that biology works!
  - COGlory 5y ago
    It blows my mind every day. And this is what I do for my career.

Does 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 ago

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/ https://zlab.umassmed.edu/benchmark/ [1] https://en.wikipedia.org/wiki/Intrinsically_disordered_proteins https://en.wikipedia.org/wiki/Intrinsically_disordered_prote...

gilleain 5y ago

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 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).

andy_ppp 5y ago
It really does seem so incredibly unlikely that biology works!
- COGlory 5y ago
  It blows my mind every day. And this is what I do for my career.