Title text: Check it out--when I tug the C-terminal tail, the binding tunnel squeezes!
| This explanation may be incomplete or incorrect: More info on protein folding, expansion on [email protected], possible expansion on title text explain.|
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In this comic, Cueball is asking Megan what she does, to which she replies that she works on software to predict protein folding. This is a reference to one of a number of folding prediction software programs, some of the most well known are [email protected], [email protected] 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 rigid, 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 it is a hard problem, and Megan's reply indicate that she believes that this is the hardest problem anyone can imagine today - although someday there may come an even harder one. Cueball then asks Megan why is it such a hard computational problem, and Megan replies that it is like folding a live crane, not just a paper crane. That is because a protein cannot fold to an abstract representation of its native fold (analogous to how a paper crane abstractly resembles the live crane) - it 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 3^198 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 spontaneously on a millisecond or even microsecond time scale. This paradox is central to computational approaches to protein structure prediction.
Cueball asks whether he can make cuts during the folding process, as if this would then make folding a living crane somehow possible. Megan replies "if you can fold a Protease enzyme", an analogy to saying "if you can fold yourself some scissors". Protease enzymes are proteins whose job it is to break down (i.e. cut) other proteins, often in very specific ways. They are thus analogous to extremely specialized scissors. The meaning of this is that if, when trying to predict the folding trajectory in nature of protein A, one allows to make cuts - one is making the assumption that the Protease that cut protein A is already folded and functional. In other words, making cuts while folding just changes the question to how the protease doing the cutting was folded. Insulin is one such protein which begins as a single polypeptide chain before being cut into two chains by proteases (which then join together by disulfide rather than by peptide bonds).
In origami, purists [] considered it as cheating if you cut the paper or use more than one sheet of paper, which is why Cueball asks if cuts are allowed.
The title text refers to the result of folding a paper crane in origami. 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.
[email protected] ([email protected]) 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 [email protected] software, 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.
Please be aware that modern computers do not "waste" computing time in the same way as old ones - they dynamically reduce their clock speed and other power consumption at times of low usage. If you donate computer time, you are actually donating money to the cause in the form of your electricity bill (which sounds more convenient than via credit card anyway).
- [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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