3 ms·

Maybe this is in the supplement of the whitepaper [0], but I would have loved to see more analysis of how novel the designed proteins really are. In the whitep

by eig 2y ago

Maybe this is in the supplement of the whitepaper [0], but I would have loved to see more analysis of how novel the designed proteins really are. In the whitepaper they mention that they are novel compared to other in silico design techniques, but to my knowledge other binders to VEGF and Covid spike protein exist and would already be found in the PDB database that Deepmind trained the model on. This is not to minimize the results- if the history of ML is anything to go by, even if AlphaProteo does not currently beat the best affinity found by in vitro screens, I do not doubt that it soon will! [0] - https://storage.googleapis.com/deepmind-media/DeepMind.com/Blog/alphaproteo-generates-novel-proteins-for-biology-and-health-research/AlphaProteo2024.pdf https://storage.googleapis.com/deepmind-media/DeepMind.com/B...

vessenes 2y ago
They must be somewhat novel in that the wet lab work verified up to 10x stronger binding as predicted. I agree it would be interesting to see how they compare to known binding proteins
- dekhn 2y ago
  we've been able to design tight binders for quite some time now- the issue with synthetic designs is that they tend to bind a little too tightly. You want to have a reasonable off-rate and the ligand protein should do more than just bind, it needs to effect some sort of response from the bound protein. When you look at these synthetics they often maximize for interactions of hydrophobic areas on the surface.
gilleain 2y ago
Might depend on what your measure of 'novelty' is in protein structure. A single residue change (for example) would not normally be considered a novel structure - it's just a mutation. However, a new fold - that is, the shape that the backbone folds into - would be novel. Potentially also novel would be 'chimeric' structures with parts from other structures, as with chimeric domain swaps. There was a structure designed by the Baker lab called 'Top7 - https://pubmed.ncbi.nlm.nih.gov/14631033/ https://pubmed.ncbi.nlm.nih.gov/14631033/ that I remember as ground breaking at the time :) (in the ancient days of 2003 it seems ...)
- eig 2y ago
  Exactly. If the proteins suggested in this paper are very similar to known good binders in PDB then I am much less impressed by the results. You could argue they are generating a structure from the training set. I want more info about how novel these proteins are.

by eig 2y ago

vessenes 2y ago

They must be somewhat novel in that the wet lab work verified up to 10x stronger binding as predicted. I agree it would be interesting to see how they compare to known binding proteins

dekhn 2y ago
we've been able to design tight binders for quite some time now- the issue with synthetic designs is that they tend to bind a little too tightly. You want to have a reasonable off-rate and the ligand protein should do more than just bind, it needs to effect some sort of response from the bound protein. When you look at these synthetics they often maximize for interactions of hydrophobic areas on the surface.

gilleain 2y ago

Might depend on what your measure of 'novelty' is in protein structure. A single residue change (for example) would not normally be considered a novel structure - it's just a mutation. However, a new fold - that is, the shape that the backbone folds into - would be novel. Potentially also novel would be 'chimeric' structures with parts from other structures, as with chimeric domain swaps. There was a structure designed by the Baker lab called 'Top7 - https://pubmed.ncbi.nlm.nih.gov/14631033/ https://pubmed.ncbi.nlm.nih.gov/14631033/ that I remember as ground breaking at the time :) (in the ancient days of 2003 it seems ...)

eig 2y ago
Exactly. If the proteins suggested in this paper are very similar to known good binders in PDB then I am much less impressed by the results. You could argue they are generating a structure from the training set. I want more info about how novel these proteins are.