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Alignment Tool

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OverviewEdit

Alignment Tool Overview07:50

Alignment Tool Overview

Video Tutorial

The alignment tool lets you copy and paste the 3D structure of known proteins onto your protein in a puzzle. This is useful, because we know that evolutionarily related proteins have similar structures, and being able to copy the structure of known proteins gives us a huge headstart in folding their relatives.

We start by copying the location of the backbone atoms from the known protein into the puzzle's protein. For indentical sequences, this is easy! - we just copy the first residue of the query from the first residue of the template, the second from the second, and so on until we're done.

But we're not dealing with identical proteins - we're dealing with related proteins. Through evolution, a protein will change some of its amino acids, or delete some, and possibly insert some others. So what happens when the sequences have different amino acids? Or what if they have different lengths? There wont always be a lucine to match to a lucine, or a lycine for a lycine.

Here's where we need the idea of an Alignment. An alignment is a sort of chart where you can look up a residue in the query template, and it will tell you which residue in the template you should copy the coordinates from. In the alignment tool, the top row are the residues from our current puzzle's protein, and the letters beneath them are the residues which they will copy from.

A lot of residues will be copied from letters that dont match - this is ok. Just because the letters dont match doesn't mean that copying the coordinates is bad. But getting a letter match is a good thing. A color match is also good, but not quite as good as a letter match.

Sometimes in order to make the letters match up better, an alignment will have a gap, where there's no corresponding residue. Gaps are inserted to make the other letters and colors line up better. They are also necessary because it's rare that even related proteins will have the same length, so you'll have to have gaps somewhere.

Usually, you'll start a puzzle with an alignment that the computer generates for you. This alignment just tries to maximize the letter and color matching. It is, in a sense, very dumb. It is dumb because it ignores the 3D structural consequences of the alignment. You can match all the residues you want, but if the resulting structure doesn't work, then that alignment didn't work.

This is where humans come in. The alignment tool lets you adjust the computer generated alignment so that it makes sense structurally. The player's task is to figure out which regions of the alignment should be kept, and which parts need to be adjusted. Usually this means identifying which regions are the most crucial to the proteins structure (usually the interior, hydrophobic core), and trying to match better on those regions, while sacrificing matches in the tails or exterior loops. Then the player must figure out how to resolve these exterior regions that dont match using the standard tools of Foldit!

Note: Cutpoints were introduced April 2012 - they are explained in the tutorials - if you are having trouble seeing them switch to line in the view menu temporarily - they show up very well.

Alignment Panel - tool update 18 July 2012
* The alignment panel now has a 'score' in the title bar. This score gives you an estimate of how good your structure is. Think of it as how well your fold will do if you resolve the cutpoints and shake the structure out.
* The alignment behavior has been changed slightly. Now you can single click the align button to simply align once, and you can double click to lock to the alignment, like before. Clicking again while locked will unlock it.
* The old 'score' has been renamed 'match', as it gave the false impression that players should attempt to optimize this number (the new 'score' should be much better for this purpose).
* The alignment intro levels have been updated to reflect these changes

Partial Threading:Edit

Partial threading allows you to only copy a certain region from the template. To do a partial thread, select the letters in the query sequence that you want to thread.

Foldit Partial Threading01:46

Foldit Partial Threading

Then hit the partial threading button, near the top right of the Alignment window.

Now lock to the thread.

If you want to thread a different region, unlock from the thread, select the new letters in the query sequence, hit the partial threading button again, and then lock to the thread again.

Partial Threading - step by step

LegendEdit

Alignment tool6

Alignment Tool Legend

1. Query Sequence: The amino acid sequence of the protein you are trying to fold. The letters are colored by which amino acids have similar properties, and thus like to line up with each other. You can move the letters around by clicking on them. Double-click on a letter to select a block of letters.

2. Working Template Sequences: The amino acid sequences of templates, which are proteins whose folds are known. The brighter one is currently selected.

3. Match Quality: This row shows how well each letter matches between the query and the template(s). The bigger the white bar, the better the match. Two residues that are identical and lined up will show as a solid white square. If you line up two residues that are the same color, such as (L) Leucine and (I) Isoleucine, this will be shown by a small white rectangle. A thin white line means that there is no match between the residue in your query and the current template(s). If there is no white line then either your query or template does not match up and there is a gap in the alignment. You want to minimize gaps as much as possible, while trying to line up similar residues at the same time. If there is no active template [4], the match quality will be calculated across all working templates.

4. Active Template Selection: Check a box to select a template to activate. The active template’s structure will be visible and this is the one that will be threaded.

5. Thread: The most important button! Selecting an active template [4] allows you to use this button to thread your protein’s structure onto the structure of the active template sequence. This will take a while, but once it has been able to thread successfully the Thread Tool in the top left of your screen will change from “Stop Threading” to “Accept Thread”. At this point it will continue to try threading even further, until it has found the best possible thread. You can click “Accept Thread” at any time to use the current thread. If it is unable to thread it will stop and a display “Can’t thread from alignment”. If this happens certain letters in the query sequence will blink red; this is the region preventing it from threading successfully. Resolve any gaps around these red blinking letters and try threading again.

6. Reset Alignment: You can reset the alignment to what it was when you first loaded the puzzle.

7. Undo / Redo Move: If you moved part of a sequence in the alignment tool (either the query sequence or a template sequence) you can undo or redo the move.

8. Template Reserve: Because it is often easier to compare alignments one at a time, templates are kept in this Reserve. You can look at their sequence, score and name [16] while in the reserve before comparing them to your query.

9. Number of current templates in Reserve: This counter shows you the current template in the reserve as well as the total number of sequences that you have in the Reserve.

10. Cycle through Reserve: Use the blue arrows to cycle through the sequences of the templates in the Reserve.

11. Move up from Reserve: Click this to move the current sequence in the reserve up into the working sequences. You can move up to 5 sequences out of the Reserve.

12. Replace all with current Reserve sequence: Click this to replace all the working sequences with the current sequence in the Reserve.

13. Move down to Reserve: Click this to move a working sequence down to the Reserve.

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.

16. Template Name/Score: By clicking on this button you can toggle between the information displayed in [17].

17. Alignment Score/Template Name: This area will show either the alignment score, which shows how good the current alignment is between that sequence and the query, or the template name, which you can use to identify each template.

See a demonstration video

Foldit Sequence Alignment Structure03:53

Foldit Sequence Alignment Structure

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