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