Give us proteins w/o pre-folded tertiary structure

Case number:845799-986548
Topic:Biochem
Opened by:Madde
Status:Closed
Type:Suggestion
Opened on:Tuesday, July 21, 2009 - 18:48
Last modified:Tuesday, August 18, 2009 - 22:19

Quote from blog-post http://fold.it/portal/node/986513
"It's good to explore, and to actually move the protein in significant ways. you may get more points with hard-to-notice shakes and wiggles, but to truly explore better solutions one must venture into the unknown."

Well, if you want us to 'venture into the unknown' then don't give us proteins with pre-folded tertiary structures. Hand out to the advanced folders proteins with the predicted secondary structures only (see picture) and put the pre-folded proteins in the (<150) and (<15) puzzles.

Unfolded proteinUnfolded protein

(Tue, 07/21/2009 - 18:48  |  14 comments)


Vman's picture
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That makes a lot of sense to me. Now we can be able to form our own tertiary structure w/o the protein always reverting to its previous state when you perform a wiggle. I think the dev team should implement this soon.

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wouldn't one wiggle long enough to stop the puzzle gaining points make you end up with a folded stucture anyway?

You might know it's not correct, but you also have that knowledge when you start working on any puzzle, "prefolded" or not.

Doesn't mean I don't like the idea, I'd love to start with a puzzle that has no tertiary structure. I guess the strategy would be to work on it for a while, before ever touching the wiggle button.

Vman's picture
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Nicky, the wiggle won't take it to a regular pre-folded structure necessarily because the protein won't have any mojo at all. Mojo causes proteins to revert to their original state after a a change has taken place.

beta_helix's picture
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I believe that this was tried last summer as a puzzle, but if there is enough demand for such a puzzle we can easily provide one.

I think the only reason we have not posted an extended chain conformation was that it might frustrate many players.

Hopefully Foldit now has enough tools to properly fold up a protein from scratch, and the Quest to the Native puzzles will have given everyone examples of what native proteins looks like.

I will bring this up at our weekly meeting if this is something that the Foldit community wants to try out!

Joined: 12/14/2008

No, the wiggling wpould not make the protein to a shape.

infjamc did it on one of the last puzzles, he did a 100% helix structure in one line - and even scored quite good with this. ^^ Very interesting. I played around with it a bid and it didn't revert to a normal structure at all.

I would like the idea - but give it enough time!

Vman's picture
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We could have an intro that explains how to fold a protein from scratch. Like a small protein that would be easy to fold could be used as an example.

beta_helix's picture
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we now have a puzzle starting from a fully extended chain!
http://fold.it/portal/node/986655
we hope you all enjoy it!

maybe we can release de-novo CASP targets this way (targets where there are no similar solved structures to use as a template)

spvincent's picture
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I like the idea of not having a preconceived notion of what the folded protein should look like but I think being given the protein in a straight line is overdoing it. I'd prefer to see the secondary structure given as Madde originally suggested: either that or, as has been done in some all-hands puzzles, give players the choice of selecting one of several initial candidate structures.

beta_helix's picture
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Thanks for the quick feedback!

We have implemented your suggestion in the next freestyle puzzle that is being released today (it's the next blind mini-CASP target).

The reason we didn't assign any secondary structure (and in certain past Foldit puzzles we have given you no secondary structure assignment) is because those aren't necessarily correct.

Secondary Structure Prediction used to have its own category at CASP, and there are many difference methods for predicting the secondary structure of an unknown protein:
http://www.bmm.icnet.uk/people/rob/CCP11BBS/secstrucpred.html

It is a lot more accurate than tertiary structure predictions, but it is still not exact (especially with difficult targets) so we don't want players thinking that the secondary structure is set in stone and shouldn't ever be changed!

Hopefully for the Mini-CASP 2-Freestyle puzzle you will all use the secondary structure assignment as a recommendation!

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Having asked for secondary structure predictions and been given them, I wonder if it's such a good idea after all :) On looking at the Freestyle Mini-CASP (186) my immediate thought was to start with the sheets and join them up in an anti-parallel way so they all lay side by side and proceed from there. Judging by some of the other structures I saw, I'm guessing that others had similar ideas. Yet this approach yielded structures that scored 500 points or so less than the slightly ugly-looking 'furball' structures (188-190) we're seeing as starting points generated by Rosetta.

I'm slightly surprised that secondary structure prediction isn't quite reliable. Intuitively you'd have thought getting this right would be a prerequisite for determining the tertiary structure.

beta_helix's picture
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Yes, this is one of the harsh lessons in protein structure prediction and why we were reluctant to assign secondary structure.

One of the main problems is that most secondary structure predictions return how confident they are with a certain secondary structure element, but this is hard to translate in the game.

For example, the SAM-T08 server (http://compbio.soe.ucsc.edu/HMM-apps/HMM-applications.html) reports these cool sequence logos (I have attached the sequence logo for SAM_T08's mini-CASP2 secondary structure prediction) where the red H is for helix, green E for sheets, and C for loops (coils).

In these sequence logos, the higher the letter is for a given amino acid, the more confident the prediction is.
For example, at residue 60, the F (Phenylalanine) is strongly predicted to be in a helix (and indeed all three Rosetta@Home solutions and the freestyle puzzle have a helix for Phenylalanine 60).

But the P (Proline) at residue 31 basically has an equal prediction of being in a sheet or a loop (the green E and grey C have about the same height) so all we can take from this is that it is most likely not a helix.

It could be interesting to incorporate these different confidences into the game (coloring secondary structure elements by how confident the predictions are) but the game might get even busier than it already is!

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You could post the sequence logos in a comment at the puzzle's page.
By the way, there is no attached sequence logo within your posting. Maybe this is caused by the bug I reported earlier: http://fold.it/portal/node/986615

beta_helix's picture
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Great idea, Madde... it seems like nobody is using the puzzle comments, so this might be a good use for it!

Can you now see the attachment in my previous post?

Madde's picture
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Yes, now I can see it.
Thank you!

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