puzzle picture
390: Unsolved monkey virus protein
Status: Closed

Summary

Name: 390: Unsolved monkey virus protein
Status: Closed
Created: 12/17/2010
Points: 100
Expired: 01/07/2011 - 23:00
Difficulty: Intermediate
Description: The Folded monomer of protease from Mason-Pfizer monkey virus is currently unsolved by protein crystallographers. It was solved in 2003 by NMR, but there is a great deal of variation in those models and they don't fit perfectly with the X-ray crystallographic data. We are giving you these 10 NMR models to work on for 3 weeks, so that you have plenty of time to try out each model. We hope you can help us solve this structure! Please see the puzzle comments for more info.
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Comments

beta_helix's picture
User offline. Last seen 3 weeks 4 days ago. Offline
Joined: 05/09/2008
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Can you come up with a model that crystallographers can use?


You can see the variation in the models solved by NMR:
http://www.rcsb.org/pdb/explore/explore.do?structureId=1NSO

Our hope is that Foldit players can come up with a model that fits the more recent X-ray crystallographic data better than these NMR models from 2003. Then we could use that prediction for molecular replacement (http://en.wikipedia.org/wiki/Molecular_replacement) and solve this monkey virus protein using X-ray crystallography!

This would be an amazing scientific achievement, as we have been unable to use Rosetta to solve this particular structure using molecular replacement, but our lab has been able to do it with other proteins.

So we are giving you all 10 NMR models as starting structures (every time you reset the puzzle it will randomly select one of these 10 structures) and all 10 starts are also available in your Template Reserve in the Alignment Tool (as well as an extended chain conformation).

Even though the sequences for all 11 structures in the Alignment Tool are all identical, threading them will give you very different results. We hope that you can use partial threading to combine different regions from each NMR model.

Remember that by clicking on the 'Score' button on the top right of the Alignment Tool, you can see the name of each model ('model1', 'model2', etc., and 'extend' for the extended chain conformation) so that you can easily differentiate between the 10 different models. You can go back to the alignment score (which is useless for this puzzle since all the sequences are identical) by toggling the 'Name' button:

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
partial threading instructions

http://foldit.wikia.com/wiki/Alignment_Tool

" ...

14. Set Partial Threading: To thread a subset of your query sequence, select a region (by clicking, double clicking, or shift clicking to select more letters) in the query sequence, click this button to highlight it and thread [5].

15. Clear Partial Threading: Click on this button to clear the partial threading region you previously selected and return to the entire alignment.

..."

buttons 14 & 15 are the two gray squares above "Name" in the picture in comment #1, according to the illustration at the above link. Thank goodness for Google advanced search ;-)

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
Activate Partial Threading Button I of II

Button 14 "Set Partial Threading" is inactive (gray) until a selection is made in the top "Query Sequence" line of AA codes. A selection in the "Working Template Sequence" (the lines farther down) will **not** activate button 14. Note in the screen shot that button 14 is now bright-white instead of gray as I've made a selection (35-44 on a fresh puzzle reset of Model 4, as you can see from the score of -470.150).

When I will shortly press button 14, the AA selection of 35-44 will also show up the Model 8 Working Template Sequence, which is the template currently selected (X displayed in the "Activate Template" box to the left of the lower sequence.
Activate Partial Threading Button I of II: AAs 35-44 selected from top Query Sequence lineActivate Partial Threading Button I of II: AAs 35-44 selected from top Query Sequence line

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
Activate Partial Threading Button II of II

Now I have pressed Button 14 "Set Partial Threading". Note how the corresponding AAs 35-44 are lit up in both the top "Query Sequence" and the selected "Working Template Sequence," (the corresponding bit of the puzzle molecule flashes too). "Clear Partial Threading" to the right of "Set Partial Threading" is white now, and pressing it cancels the operation. Pressing the "Thread from active template" happy-face will now perform the partial threading.

Pardon me for belaboring the details of this procedure, but I spent a surprising amount of time incorrectly trying to make this work with futile selections in the (lower) selected working template and would like to save others the frustration.

beta_helix's picture
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Joined: 05/09/2008
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Thanks gramps!

Thank you for that, we really should move the Alignment Tool explanation to the FAQ or somewhere more visible!

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
Mystery Model

When I restart this puzzle I get one of the 10 models (0,1,...,9) but the start score isn't the same as any of the post-threaded scores for the models in the reserve.

How can I tell which model I have after I randomly reset? The ten possible starting scores (exclusive of "extend") are

A) -2844.163
B) -6889.592
C) -4259.602
D) -2499.298
E) -4012.628
F) -3134.392
G) -3847.071
H) -2166.369
I) -5740.561
J) -470.151

Mark-'s picture
User offline. Last seen 10 weeks 2 days ago. Offline
Joined: 08/05/2009
Groups: Contenders
Add to the feedback

It can be very difficult, if not impossible, on puzzles that have many similar alignments. There is a feedback post regarding this issue http://fold.it/portal/node/988843 if you would like to add a comment to it.

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
Gotcha!

Start scores of the models as they come up in the random resets:

Model 0: -2166.368
Model 1: -4259.601
Model 2: -2844.162
Model 3: -5740.560
Model 4: -470.150
Model 5: -3847.070
Model 6: -2499.297
Model 7: -6889.591
Model 8: -3134.391
Model 9: -4259.601

======================
This is truly ugly. In puzzle 390 each of the Models has a slightly different structure. After you've threaded from one of the models the following source code does fifty puzzle resets (destroying your present position!) and puts the start-score of any resets with the current structures into the Recipe Output. If you're really unlucky you might have to run it twice to get the random hit.
=======================
-- Report Reset of Current Structure destructive v0.01; prints start scores of resets that match
-- current structure (**warning** destructive script doesn't restore current)
local string current_structure={} -- table of present structure codes for all segments
do -- start constructor for table current_structure
for x=1,get_segment_count() do
current_structure[x]=get_ss(x)
end
end -- constructor for table current_structure
for x=1,50 do -- number of resets, these come up randomly
reset_puzzle()
local boolean same_structure=true
for y=1,get_segment_count() do
if current_structure[y] ~= get_ss(y)
then
same_structure=false
end
end
if same_structure
then
print(get_score(true)) -- present game score, including negative scores
end
end

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
corrected start scores table for the models

Start scores of the models as they come up in the random resets:

Model 0: -2166.368
Model 1: -4012.627 **corrected**
Model 2: -2844.162
Model 3: -5740.560
Model 4: -470.150
Model 5: -3847.070
Model 6: -2499.297
Model 7: -6889.591
Model 8: -3134.391
Model 9: -4259.601

spvincent's picture
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Joined: 12/07/2007
Groups: Contenders
This is ugly

I nominate this protein as the inaugural entry in the ugly proteins gallery: this might be the companion blog to Mike Tyka's beautiful protein blog. See http://beautifulproteins.blogspot.com/

gramps's picture
User offline. Last seen 3 years 28 weeks ago. Offline
Joined: 12/16/2010
it's the code that's ugly

I didn't mean to judge the protein, it's the desperate recipe code to indirectly find which model is which in the random resets that only a parent could love.

Joined: 08/06/2010
Groups: Contenders
Actually, I like your code

gstart={
{0, -2166.368},
{1, -4012.627},
{2, -2844.162},
{3, -5740.560},
{4, -470.150},
{5, -3847.070},
{6, -2499.297},
{8, -3134.391},
{9, -4259.601}
}
gss={}
for j=1,get_segment_count() do
gss[j]={[L]=0,[H]=0,[E]=0,[M]=0}
end
local startsFound=0
repeat
reset_puzzle()
local i = 0
repeat
i=i+1
until (gstart[i]%1)==(get_score(true)%1)
if gstart[i][3] == nil then
startsFound=startsFound+1
gstart[i][3]='found'
for j=1,get_segment_count() do
ss=get_ss(j)
gss[j][ss]=gss[j][ss] + 1
end
until startsFound=10
-- Now if my code is correct
-- you have a vote on secondary structure.
-- you don't need to have the scores preloaded
-- but what the heck. Do you want a vote on
-- segment distances as well? You might be
-- able to band to those distances.

Joined: 08/09/2010
X-ray data.

You tell us the NMR data does not fit perfectly with the X-ray data, and give us the NMR templates and graph, but no information about the X-ray data. I believe, depending on the resolution in Angstroms of the X-ray data, it is possible to determine secondary structure, but that loops tend to be undetermined. Can you tell us the resolution of the X-ray data and what secondary structure information was extracted from it, or any other information you can give us to help fold this mysterious protein?

beta_helix's picture
User offline. Last seen 3 weeks 4 days ago. Offline
Joined: 05/09/2008
Groups: None
prot-bustr,

In general, secondary structure composition can't be determined from unphased crystal data. There are some exceptions with all-helical proteins (http://www.nature.com/nmeth/journal/v6/n9/full/nmeth.1365.html)

What we are hoping will work with Foldit is what was done previously using Rosetta: (http://www.nature.com/nature/journal/v450/n7167/abs/nature06249.html).

Most likely, the topology & secondary structure of the protein is pretty similar in the X-ray structure as in the NMR structure. Molecular replacement generally fails above 2A RMS so the target may not be very far from the NMR ensemble. That said, there may be some reorganization due to crystal contacts ... but sadly we really don't know.

Joined: 09/16/2010
Groups: None
Links requiring monetary

Links requiring monetary payment are not helpful to me.
What might be helpful would be a link to X-ray structure.

beta_helix's picture
User offline. Last seen 3 weeks 4 days ago. Offline
Joined: 05/09/2008
Groups: None
my apologies, here is that paper:

Sorry about that, you can download the pdf from the Baker Lab webpage:

http://depts.washington.edu/bakerpg/drupal/node/115

You'll find the Foldit nature paper there as well, if you didn't get a chance to read it:

http://depts.washington.edu/bakerpg/drupal/node/16

If you want to look at some X-ray structures that might be familiar to you, you can go to the CASP9 target page:
http://predictioncenter.org/casp9/targetlist.cgi

and click on the blue PDB code on the right for any of the targets that have been solved using X-ray crystallography (those are denoted by the 4th column on the CASP page saying "X-RAY")

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
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