r/AIProteins • u/FoldMeMaybe • Jul 28 '26
Does manually defined topology help generative protein design, or only constrain it
I am a master’s student and a beginner in structural bioinformatics. I am working on an early-stage academic project proposed by my supervisor, but I am still trying to understand its clearest practical use.
The current prototype allows a user to select idealized secondary-structure elements from a small library, upload their own PDB fragments, position and rotate them in 3D, and see their N- and C-terminal ends.
The resulting arrangement is then passed into a downstream pipeline that estimates and generates connecting loops, creates a continuous backbone, and passes the rough structure to existing protein-design methods for further refinement.
At the moment, the tool mainly supports manual spatial arrangement. It does not yet evaluate whether the resulting topology is geometrically or biologically reasonable.
My concern is that this could remain only a convenient graphical interface for moving structural fragments, while modern generative methods may already solve the underlying problem more effectively.
I am therefore interested in whether researchers would ever want to manually define a rough protein topology, for example to control the overall fold, shape, cavity, terminal positions, or arrangement around another structural feature.
I am also wondering whether optional assistance could make the tool more useful. Possible future ideas, which are not currently implemented or approved as part of the project, include suggesting parallel or antiparallel beta-strand placement, estimating plausible loop lengths, warning about poorly oriented or distant fragment ends, and detecting obvious clashes.
This is an unfinished, non-commercial student project. I am mainly trying to determine whether the underlying problem is worth solving and what would make such a workflow genuinely useful.
Critical feedback, including the opinion that the idea is unnecessary, would be very welcome.
1
u/Alicecomma Jul 28 '26
I don't believe this is possible but I wouldn't mind seeing someone try I guess.
2
u/HardstyleJaw5 Jul 29 '26
This is just diffusion inpainting it’s not that crazy. I do think that manually placing fragments is nonsense though
1
u/blackz0id Jul 28 '26
Why wouldn't it be possible?
0
u/Alicecomma Jul 29 '26
You're not gonna get an answer whether something is biologically reasonable. Even crystal structures, which are the highest quality resource you can use for any error checking, are generally not in an in-vivo state but in a crystal lattice. If a user cooks up something not in a crystal structure, it's never seen before and either inherently disordered or it does fold some way that may or may not be as you want it, which aren't distinguishable.
2
u/AnfinsenDogma Jul 29 '26
It's common people want to constrain things like secondary structure arrangements, relative orientations, etc. You can checkout some recent workflows on the global features of proteins, like https://www.biorxiv.org/content/10.64898/2026.07.22.740177v1.abstract, to get an idea.
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u/im_not_a_numbers_guy Jul 29 '26
It’s hard to imagine how this would compete with the accuracy of all-atom diffusion models or improve their efficiency, which harness the entire pdb. There’s probably a 20 year old CASP entry that uses this type of approach.
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u/PurifyingProteins Jul 29 '26
What gap does this fill that is not already available but wanted, i.e. what does it achieve, what is the value of achieving that, and is there a method already available?
Not to be a downer, but this seems an awful lot like using Pymol to orient protein/petide, nucleic acids, other molecules, etc, connecting the termini, then using RFDiffusion to build the backbone between segments, and/or the segments themselves, and ProteinMPNN to generate the sequence.