1440: Aflatoxin Challenge: Round 1

Closed since over 8 years ago

Summary

• Created: October 13, 2017
• Expires: October 31, 2017 at 23:00 UTC
• Max points: 100

Description

Aflatoxins are a class of poisonous compounds that contaminate a significant portion of the global food supply. In this puzzle, players are challenged to redesign an enzyme that could break down aflatoxin molecules. The majority of the protein is frozen, with the aflatoxin ligand fixed in a binding pocket. Surrounding the binding pocket are a number of loops that might be redesigned without affecting the folding stability of the protein. In these loops, players may manipulate the protein backbone and mutate the residue sidechains. Redesign the loops of this protein to better bind the aflatoxin ligand!



This is the first puzzle of our Aflatoxin Challenge, sponsored by Mars Inc. and Thermo Fisher Scientific. Promising designs will be tested by the Siegel Lab at UC Davis. By participating in the challenge/game, the players agree that all player designs will be available permanently in the public domain, and the players will not seek intellectual property protection over the designs created as part of the challenge/game.



Note: Due to special interest in this puzzle, the deadline has been extended by one week, to October 31 at 23:00 UTC.

Top groups

• 21. Alpha Rays 1 pt. 9,897
• 22. DSN @ Home 1 pt. 9,816
• 23. xkcd 1 pt. 9,766
• 24. Team South Africa 1 pt. 9,647
• 25. Rechenkraft.net 1 pt. 9,559
• 26. Piratenpartei Deutschland 1 pt. 9,556
• 27. FoldIt@Netherlands 1 pt. 8,501
• 28. 2017-2018 Mr Lipin 8-1 Science 1 pt. 8,491
• 29. Biochem-AD17 1 pt. 8,440
• 30. LS Pro Folders 1 pt. 5,362

Top soloists

• 1. LociOiling 100 pts. 16,065
• 2. reefyrob 99 pts. 15,990
• 3. Timo van der Laan 97 pts. 15,894
• 4. Enzyme 95 pts. 15,875
• 5. eusair 93 pts. 15,860
• 6. spvincent 91 pts. 15,849
• 7. Mike Cassidy 90 pts. 15,842
• 8. Bruno Kestemont 88 pts. 15,825
• 9. johnmitch 86 pts. 15,816
• 10. retiredmichael 85 pts. 15,794

Comments

[Susume]

I think the only difference is that where ours has an OH (25, 38) and an oxygen with the calcium ion (23, 24), the B1 has only a single O. All the rest is the same. The reason the bonds look different is that foldit draws rings with double bonds all the way around as a convention, while JMol uses a different convention and draws some as double and some as single. The Baker lab scientists who were at the launch event explained this to me when I asked why the carbons in our ligand look like they have more than 4 bonds each.

They also said the ligand we were given is an aflatoxin that has been partly metabolized - that's how it gains the extra OH and the calcium. Edit to add: after re-reading rmoretti's comment on a recent feedback, I realize I completely misunderstood about the state of the ligand. It's not partly metabolized - it's a transition state - see s0ckrates' helpful analogy below for what that means, because I haven't really got a clue.

[LociOiling]

The Foldit convention of doubling all the bonds in a ring kind of makes sense. There's something about how there aren't quite enough electrons to go around, and they end up being shared among all the atoms in the ring. I think this case is sometimes represented as a hexagon with a circle inside it, but that may be something else. (Getting tired of looking things up on wikipedia.)

Nothing like getting used aflatoxin. Seems like par for the course. Other games probably have nice fresh aflatoxin to work with.

On a related (?) front, the ring where the calcium is attached in ours is probably the lactone group that's the target. Not sure if it could still be considered a lactone, due to the changes Susume has noted, but I personally don't need another funky/weird chemical name at the moment.

Speaking of chem names, the oxygen, carbon, and three hydrogens on the lower right of both images above is a methoxy group, which you may see as OMe on some diagrams. Or if you prefer, it's a methyl group (the CH3 part), also known as Me, bound to oxygen (O).

Phew, I need to rest for a bit.

[LociOiling]

Here are the details of the "propeller" shape of the protein this puzzle.

[img_assist

nid=2004366

title=PDB id 3DR2 propeller blades

desc="beta propeller" seen in puzzle 1440

link=popup

align=left

width=640

height=618]

As described previously, there are six "blades" on this propeller. Each propeller has at least four sheets (or four "beta strands" if you're writing for publication). Three blades have an extra sheet taken from the "N-terminal domain", or the beginning part of the protein.

Blade six is a further exception. It actually has two of its sheets (strands) from the N-terminal domain. It's where the fourth N-terminal sheet mentioned in the abstract for 3DR2 is hiding. The first three sheets are attached to blades 1, 6, and 5, respectively. Then the N-terminal domain reverses course into a helix. The fourth N-terminal sheet ends up bound to the second one, forming the outer two sheets of blade 6 in this diagram.

N-terminal stuff aside, each blade is made from consecutive sheets arranged in a back-and-forth "anti-parallel" style. (Or maybe, "boustrophedonically".) The outer sheet from each blade goes into a somewhat long section of loop, crossing over to start the inner sheet of the next blade.

The blades in this protein are not at all the same, so it would make pretty shaky propeller. There's a small helix between the innermost two sheets of blade 1. Blade 3 has a much larger and very bent helix between its middle two sheets. (The dividing line I've drawn goes through this helix, but it's all part of blade 3.) That and the whole N-terminal part would throw the whole thing way out of balance.

There's nothing magic (or scientific) about how I numbered the blades here, but they are in segment order, except for the N-terminal contributions.

This image was captured from JMol. The annotations were done in Paint Shop Pro, which also handled the screenshots. It's not clear to me how much this information helps with folding, but it's kind of interesting in its own right.

[Skippysk8s]

Thanks to Loci for all the information. I'd found the JMOL info, but must admit I'm still a bit lost about what to do with this for a "good science" answer. I'd recommend we let the puzzle close first – and then perhaps show some examples of how to solve this usefully
I can get solutions that bond the 3DR2 to the ligand, but they don't score well. I have ancient and limited chemistry background, so something directed at what sorts of things to work on before the next scoring puzzle would be really useful. Short of adding the dimer – that would put the puzzle size beyond my machine
I'd be happy to contribute to a thread of questions after the close
Skip

[DoctorSockrates]

I come from a gamer and science background, so here's my time to shine.

The protein we're working on here is an enzyme if I remember correclty, and part of an effective enzyme is stabilizing the "transition state" of its substrate.

Say we were trying to make an enzyme to snap a stick in half. The "transition state" would be a bent, but not snapped, stick. If we designed the enzyme to be able to have a super stable "bent stick state" (which is actually what we have in puzzle 1440, a transition state of aflatoxin), then it can do its job better. The bent stick state needs less energy to snap the stick then the normal stick state, and the enzyme's usual job for catalyzing is

To have a stable bent sti–er transition state, we just follow mostly the same rules for Foldit, except we're not so much concerned with blue/orange placement but we're more so focused on packing the aflatoxin in nice and cozy (minimize voids, that is) and hydrogen bonding the hell out of aflatoxin (to hold it in place for that "bent stick state") with a whole bunch of your polar blue boys ready to go.

[smortier]

The team has decided to release the results around mid-December when the aflatoxin challenges end. This way, no player can gain an advantage by viewing other players' solutions.

[avika152]

Nice.