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[return to "AlphaFold reveals the structure of the protein universe"]
1. COGlor+JD[view] [source] 2022-07-28 15:03:35
>>MindGo+(OP)
Before my comment gets dismissed, I will disclaim I am a professional structural biologist that works in this field every day.

These threads are always the same: lots of comments about protein folding, how amazing DeepMind is, how AlphaFold is a success story, how it has flipped an entire field on it's head, etc. The language from Google is so deceptive about what they've actually done, I think it's actually intentionally disingenuous.

At the end of the day, AlphaFold is amazing homology modeling. I love it, I think it's an awesome application of machine learning, and I use it frequently. But it's doing the same thing we've been doing for 2 decades: pattern matching sequences of proteins with unknown structure to sequences of proteins with known structure, and about 2x as well as we used to be able to.

That's extremely useful, but it's not knowledge of protein folding. It can't predict a fold de novo, it can't predict folds that haven't been seen (EDIT: this is maybe not strictly true, depending on how you slice it), it fails in a number of edge cases (remember, in biology, edge cases are everything) and again, I can't stress this enough, we have no new information on how proteins fold. We know all the information (most of at least) for a proteins final fold is in the sequence. But we don't know much about the in-between.

I like AlphaFold, it's convenient and I use it (although for anything serious or anything interacting with anything else, I still need a real structure), but I feel as though it has been intentionally and deceptively oversold. There are 3-4 other deep learning projects I think have had a much greater impact on my field.

EDIT: See below: https://news.ycombinator.com/item?id=32265662 for information on predicting new folds.

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2. mupuff+HE[view] [source] 2022-07-28 15:08:42
>>COGlor+JD
> There are 3-4 other deep learning projects I think have had a much greater impact on my field.

Don't leave us hanging... which projects?

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3. COGlor+yJ[view] [source] 2022-07-28 15:29:48
>>mupuff+HE
1) Isonet - takes low SNR cryo-electron tomography images (that are extremely dose limited, so just incredibly blurry and frequently useless) and does two things:

* Deconvolutes some image aberrations and "de-noises" the images

* Compensates for missing wedge artifacts (missing wedge is the fact that the tomography isn't done -90° --> +90°, but usually instead -60° --> +60°, leaving a 30° wedge on the top and bottom of basically no information) which usually are some sort of directionality in image density. So if you have a sphere, the top and bottom will be extremely noisy and stretched up and down (in Z).

https://www.biorxiv.org/content/10.1101/2021.07.17.452128v1

2) Topaz, but topaz really counts as 2 or 3 different algorithms. Topaz has denoising of tomograms and of flat micrographs (i.e. images taken with a microscope, as opposed to 3D tomogram volumes). That denoising is helpful because it increases contrast (which is the fundamental problem in Cryo-EM for looking at biomolecules). Topaz also has a deep learning particle picker which is good at finding views of your protein that are under-represented, or otherwise missing, which again, normally results in artifacts when you build your 3D structure.

https://emgweb.nysbc.org/topaz.html

3) EMAN2 convolutional neural network for tomogram segmentation/Amira CNN for segmentation/flavor of the week CNN for tomogram segmentation. Basically, we can get a 3D volume of a cell or virus or whatever, but then they are noisy. To do anything worthwhile with it, even after denoising, we have to say "this is cell membrane, this is virus, this is nucleic acid" etc. CNNs have proven to be substantially better at doing this (provided you have an adequate "ground truth") than most users.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623144/

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