1430: Proteins

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Proteins

Title text: Check it out--when I tug the C-terminal tail, the binding tunnel squeezes!

Explanation

In this comic, Cueball is asking Megan what she does, to which she replies that she works on software to predict protein folding. There are many folding prediction software programs. Some of the most well known are Folding@Home, Rosetta@Home and FoldIt.

Protein folding is the process by which proteins, which are floppy, unstructured chains of amino acids when initially synthesized in a cell, assume a stable, functional shape. If the folding process does not complete, or completes incorrectly, the resulting protein can be inactive or even toxic to the body. Misfolded proteins are responsible for several neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease, as well as some non-neurodegenerative diseases such as cardiac amyloidosis.

Cueball asks Megan if that is a hard problem, to which she replies, that someday someone may find a harder problem. Thus she indicates that at present time, this is the hardest problem in the world! That is saying a lot.

Cueball then asks Megan why it is such a hard computational problem; Megan's response is to ask Cueball if he's ever folded paper to make a crane. When he responds in the affirmative, she then compares the problem of predicting protein folding to creating a living crane by the paper-folding process. The analogy is that a protein cannot just fold to a figurative representation of a bio-molecule, the way a paper crane superficially resembles a live crane; the protein must assume an exact, perfect fold in order to be functional.

Levinthal's paradox is a thought experiment, also constituting a self-reference in the theory of protein folding. In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the molecule has an astronomical number of possible conformations. For example, a polypeptide of 100 residues will have 99 peptide bonds, and therefore 198 different phi and psi bond angles. If each of these bond angles can be in one of three stable conformations, the protein may misfold into a maximum of 3¹⁹⁸ different conformations (including any possible folding redundancy). Therefore, if a protein were to attain its correctly folded configuration by sequentially sampling all the possible conformations, it would require a time longer than the age of the universe to arrive at its correct native conformation. This is true even if conformations are sampled at rapid (nanosecond or picosecond) rates. The "paradox" is that most small proteins fold to their proper conformation spontaneously, on a millisecond or even microsecond time scale. This paradox is central to computational approaches to protein structure prediction.

As Cueball mentally turns over the hypothetical process of folding paper to make a living crane, he wonders if he is allowed to perhaps "cut" the paper to make more complicated folds available. In origami, purists [1] considered it as cheating if you cut the paper or use more than one sheet of paper, which is why Cueball asked if he was 'allowed' to do such in the hypothetical exercise they are discussing.

Megan replies "if you can fold a Protease enzyme;" these are proteins whose job it is to break down (i.e. "cut") other proteins, often in very specific ways. In this manner, Protease enzymes are analogous to extremely specialized scissors, so Megan is effectively saying "You can make cuts if you can fold yourself a pair of scissors." Of course, when trying to predict the folding trajectory in nature of a protein A, and one is allowed to make cuts during the process, one is making the assumption that the Protease that cut protein A is already folded and functional. In other words, making cuts while folding might actually make the process more complicated, not less, as now you have to consider how the cutting enzyme is folded, too.

The title text refers to the result of folding a flapping bird in origami. By pulling the tail, the head will move forward and down. However, since the joke is about folding proteins, this idea is extrapolated to include the folded proteins. The C-terminus (end of the protein chain), in this case analogous of the tail, if "pulled" would cause a created cavity or tunnel to squeeze, much like pulling a knot would do the same. In general, protein conformational changes where parts of a protein change shape as a result of pushing or pulling on another part of the protein are common in biological systems (eg, allosteric regulation, cooperative binding).

Folding@Home (F@H) is a distributed computing project which aims to simulate protein folding for research purposes. Rather than the traditional model of using a supercomputer for computation, the project uses idle processing power of a network of personal computers in order to achieve massive computing power. Individuals can join the project by installing the F@H software (there is also a web version that can be run using Google Chrome) and are then able to track their contribution to the project. Individual members may join together as a team, with leaderboards measuring team and individual contributions.

Note that most modern computers do not "waste" computing time as much as older ones. They dynamically reduce their clock speed and other power consumption at times of low usage. If you donate computer time, you are probably also donating a bit of money to the cause in the form of your electricity bill. Many people consider this to be more fun, convenient and efficient than donating via credit card.

Transcript

[Cueball is talking with Megan.]

Cueball: What do you do?

Megan: I make software that predicts how proteins will fold.

Cueball: Is that a hard problem?

Megan: Someone may someday find a harder one.

Cueball: Why is it so hard?

Megan: Have you ever made a folded paper crane?

Cueball: Yeah.

Megan: Imagine figuring out the folds to make an actual living crane.

Cueball: ...just folds? Can I make cuts?

Megan: If you can fold a protease enzyme.

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Discussion

If this comic has motivated anyone to join in with the Folding@Home project, you can get started here. --Pudder (talk) 09:28, 6 October 2014 (UTC)

I've been folding for about a year now. Before that it was the SETI@Home project - but I decided to switch to something that could have more direct and beneficial results. Jarod997 (talk) 13:58, 6 October 2014 (UTC)

Is there an xkcd team on any of the distributed computing projects? Or does someone want to put one together? Nealmcb (talk) 22:02, 6 October 2014 (UTC)

I would like to join a team RecentlyChanged (talk)

That link sends me to a "site can't be reached" thing. I googled "Folding@Home" and got a different website (https://foldingathome.org/) but I also don't participate in folding@Home so I don't know if this is real or not. Tsumikiminiwa (talk) 04:10, 17 August 2022 (UTC)

This comic has some similarities to 1425: Tasks. It can be difficult for the public (or experts for that matter) to grasp the complexity of a task for a computer. --Pudder (talk) 09:13, 6 October 2014 (UTC)

Surely if you were folding yourself a crane out of paper then you would need to fold yourself a pair of scissors in order to be able to make cuts. --141.101.99.49 10:27, 6 October 2014 (UTC)

Surely the "pull the tail" is referring to the flapping bird origami, which is similar to the crane but lacks one set of folds that make the figure narrower. 108.162.219.116 (talk) (please sign your comments with ~~~~)

Thanks for adding that "your actually donating your electricity" part - I had not considered it to that extent. I realized that the program is using more CPU/GPU "loading" while the screen saver is active, but for some reason I didn't translate that into more money out via my electricity bill. :) Jarod997 (talk) 13:58, 6 October 2014 (UTC)

No mention yet of the fact that Megan (and Randall) thinks this is the hardest problem! I have added some where it only aims at other science questions. But she did not say anything about science. Solving all human crises like overpopulation, climate, pollution, hunger, war and death could also be seen as either several or just one (unified) problem. She would then still think her problem harder... Should that be added as well in some form? I will leave that for others to decide. Kynde (talk) 18:31, 6 October 2014 (UTC)

I think it is clear that Megan means computational problems - unifying gravity or solving human crises have not been reduced to computational terms - so the comparison is not appropriate and the comment in the explaination is unwarranted. 173.245.52.157 (talk) (please sign your comments with ~~~~)

The Title Text made me think of Rembrandt's painting The Anatomy Lesson, where the lecturer was pulling a tendon in a cadaver's forearm, making a finger move. It might make an appropriate metaphor: Today's scientists are taking baby steps in learning the "anatomy" of proteins through trial and error, much like the scholars of the past deciphering the basics of the human anatomy. Aiw (talk) 21:38, 6 October 2014 (UTC)

I think the last few paragraphs about the simulation program and cpu cycles are unnecessary. Perhaps create a trivia section? Benjaminikuta (talk) 04:51, 8 October 2014 (UTC)

I agree, they don't really contribute anything to the explanation, but are somewhat related. --Pudder (talk) 07:52, 8 October 2014 (UTC)

I agree, too. Perhaps move them to comments section. Anyway, there's a Game with a purpose on a similar topic, RNA folding EteRNA. It's a little strange to play because the underlying reality is unusual, but interesting and somehow trickily entertaining. --MGitsfullofsheep (talk) 11:06, 8 October 2014 (UTC)

Serious TED talk "protein folding problem: a major conundrum of science": http://youtu.be/zm-3kovWpNQ Jorgbrown (talk) 20:52, 24 February 2015 (UTC)

Serious TED talk about advanced math making detailed Origami figurines by doing nothing but folding => http://youtu.be/NYKcOFQCeno Jorgbrown (talk) 20:59, 24 February 2015 (UTC)

Going to start using the Folding@Home Chrome web applet. Having seen the mentions here of forming an xkcd/explainxkcd team, I'm all for it! Boct1584 (talk) 01:46, 20 April 2015 (UTC)

I find this explanation a bit too technical. For all I know, there's no simpler way to explain this. Not going to add an incomplete tag, but maybe someone someday will see this and try to fix it. 162.158.255.84 22:26, 22 August 2015 (UTC)

I wonder if we could theoretically prevent computers from becoming self-aware by inputting a line that makes any processing power that is not being used work on folding@home or work on finding prime numbers or something. Then that line of code could be linked to a boolean that allows the computer to do something vital, like this: bool a=false; int pr; some kind of function that only uses any idle memory{ while (true){ if (pr is prime){print pr; a=true;} else {pr++; a=true:} } a=false} } if (a==true){computer works} That way, if the computer tries to comment out something, it stops working and I might be overthinking this. RedHatGuy68 (talk) 02:12, 2 November 2015 (UTC)

No idea how this works, but I'm going to try to comment. When I read this the first time I thought they were talking about the construction type of crane.172.70.126.117 03:29, 9 January 2023 (UTC)

I'm not adding any useful comment, except to say that you did comment very well. Bottom-posted, added the signature, etc... Better than some do. Be proud of yourself. (And I understand your mental mismatch, even though I didn't go down the same garden path as you.) 162.158.159.47 12:23, 9 January 2023 (UTC)

While Random-ing through xkcd in 2024, I stumbled upon this one. I'm just here to note that a mere ten years later, the 2024 Nobel Prize in Chemistry went to the teams that actually solved protein folding. So problems that once seemed nearly unsolvable sometimes become tractable. -- 172.69.23.21 23:28, 23 October 2024 (UTC)