"Align Protein to Density" button is confusingly named

Case number:699969-993959
Topic:General
Opened by:alwen
Status:Open
Type:Suggestion
Opened on:Friday, November 23, 2012 - 22:29
Last modified:Tuesday, October 23, 2018 - 17:57

The "Align Protein to Density" button in the Electron Density menu actually flips the protein over inside the density.

The text on the button is confusing.

Especially since the Alignment Tool aligns the protein to the model, and the word "align" does not seem to be used in that sense at all on this button.

(Fri, 11/23/2012 - 22:29  |  14 comments)


Susume's picture
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I had my protein arranged outside of ED; hit Align button, and it flipped my protein so it was 180 degrees off from where I had it. It also translated it into the ED, which I expect, but I had to rotate every piece 180 degrees and move it to the other side of the cloud to correct it.

Joined: 06/17/2010

Yes, I found that button is ALWAYS make a flipover. Also score ALWAYS drops like hell.
If this is to help us find better place - it is a miss.

jflat06's picture
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I agree that it is confusing. The tool is designed to actually align, however, this is computationally very hard to do. I am considering removing it or renaming it to something like "center protein on density".

Susume's picture
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Given that it seems to flip the protein in space, I'm wondering if there is an extra or missing minus sign in the spatial calculations somewhere. If so, and that were fixed, the tool might be fine.

brow42's picture
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It did work on the first two or so ED puzzles, when I was already close.

PCA/SVD gives an ambiguous result, it gives the optimal axes, which are preserved on reflection. I bet susume's right. It's not a missing sign, it's a (50-50? maybe, maybe not. Have to do some monte carlo :-) chance of having a negative determinant. Easily fixed in 3-D. Maybe they just forgot that last step, and it sometimes works and sometimes doesn't for that reason?

jflat06's picture
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I can check the math again, but I think it has more to do with the nature of the things we are trying to align. Using PCA to align two point clouds has issues when the clouds are roughly rotationally symmetric around one of the basis axes. There aren't enough defining features for it to correctly determine its rotation about this axis.

Joined: 05/19/2009
Groups: Contenders

Could it be that we align the bare loop in reverse to the ED and that the button tells us we should have started at the other end in our alignments ? Because that is a situation I am wondering about now. I have it aligned pretty well, yet the score is half of the top scorers and my model gets flipped when I press that button.

Is there a way to help us start at the right end of that loop and save days of work ?

jeff101's picture
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I wonder if the "Align Protein to Density" or "Center Protein on Density"
button would work better if it operated as follows:

(1) Find the average of the protein's alpha-carbon xyz coordinates,
call this the center of the protein, and subtract the center's xyz coordinates
from all of the protein's xyz coordinates so that the center lies at the origin.

(2) Determine a set of xyz coordinates that tell how far the center of the protein
is translated from a different origin fixed within the electron density cloud.

(3) Determine a set of Euler angles that tell how much the protein is rotated
about its center in an xyz coordinate system fixed with respect to the electron
density cloud.

(4) Use the above angles and coordinates to position the protein in the electron
density cloud and note the score.

(5) Use an optimization algorithm like the Nelder-Mead Simplex Direct Search Method
(implemented in Matlab as the fminsearch command) to vary the 3 xyz coordinates in (2)
and the 3 Euler angles in (3) (6 variables in all) to find the best score it can.

While fminsearch is not guaranteed to give the global maximum score, I have seen
fminsearch give good solutions when optimizing 6 variables, so I think it would work here,
at least as well as the algorithm Foldit has been using so far. Exploiting the periodicity
of both the Euler angles and the electron density cloud, as well as varying the size of
the initial simplex, can let multiple uses of fminsearch give increasingly better scores.

For more information, please see
http://www.mathworks.com/help/matlab/ref/fminsearch.html?requestedDomain=www.mathworks.com#moreabout

jeff101's picture
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It might also be good to break the optimization into 2 layers,
like nesting fminsearch for the xyz coordinates inside fminsearch
for the Euler angles. The inner layer varies the xyz translation
coordinates and is done more often. The outer layer varies the
Euler angles and is done less often. Varying the translations more
often makes sense because the translations are just addition
operations (a faster calculation) while the rotations involve
multiplying 3x3 rotation matrices by many sets of xyz coordinates
(a slower calculation).

I would not recommend graphing the intermediate results. Just show
the protein's position for the best score at the end of the
optimization.

jeff101's picture
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Say the protein starts with all 3 Euler angles equal to 0 degrees.
Since the Euler angles give the same results every 360 degrees,
you can say the starting Euler angles are p360,q360,r360, where
p,q,r are all nonzero integers (1,2,3,4,etc.). For 3 variables,
fminsearch will make its first simplex of 4 points as follows:

(1) p360,q360,r360 & its score
(2) p378,q360,r360 & its score
(3) p360,q378,r360 & its score
(4) p360,q360,r378 & its score

This initial simplex sets the range that fminsearch will explore
for each variable. Using different values for p,q,r will explore
different ranges of angles. Small p,q,r gives a more local search.
Large p,q,r gives a more global search. For example, if p=1, the
initial simplex uses the angles 360 and 378 degrees (equivalent
to 0 and 18 degrees). Also, if p=10, the initial simplex uses the
angles 3600 and 3780 degrees (equivalent to 0 and 180 degrees).
For general p, the angles are p360 and p378 degrees. p360 is
equivalent to 0 degrees. p378 is equivalent to p360+p18 or
p18 degrees. This gives the effective angles below, which repeat
for p=21-40,41-60,61-80,etc.

p    p378
1      18
2      36
3      54
4      72
5      90
6     108
7     126
8     144
9     162
10    180
11    198
12    216    
13    234
14    252
15    270
16    288
17    306
18    324
19    342
20      0
21     18
jeff101's picture
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Say the unit cell for the electron density cloud
has x=0-60, y=0-80, and z=0-100 and the protein's
center starts at (x,y,z)=(40,60,20) in the same
coordinate system. Since the unit cell repeats
every 60 units in the x-direction, 80 units in
the y-direction, and 100 units in the z-direction,
the initial position of the protein's center is
equivalent to (x,y,z)=(40+60p,60+80q,20+100r);
that is, the initial position of the protein's
center will give the same electron density score
for any set of integers p,q,r.

If we keep p,q,r as nonzero positive integers
(1,2,3,4,etc.), the initial simplex for the xyz
coordinates for the protein's center will be as
follows:

(1) 40+60p,60+80q,20+100r & its score
(2) 42+63p,60+80q,20+100r & its score
(3) 40+60p,63+84q,20+100r & its score
(4) 40+60p,60+80q,21+105r & its score

If p=1, the initial simplex uses the x values
100 and 105 (equivalent to 40 and 45). Also,
if p=10, the initial simplex uses the x values
640 and 672 (equivalent to 40 and 12). For
general p, the x values are 40+60p and 42+63p.
40+60p is equivalent to 40, and 42+63p is equivalent
to 42+60p+3p or 42+3p. This and similar logic gives
the effective x,y,z values below, which repeat for
n=21-40,41-60,61-80,etc.

  x=42+63n y=63+84n z=21+105n
  x=42+3n  y=63+4n  z=21+5n
n x=0-60   y=0-80   z=0-100
1   45       67       26
2   48       71       31
3   51       75       36
4   54       79       41
5   57        3       46
6    0        7       51
7    3       11       56
8    6       15       61
9    9       19       66
10  12       23       71
11  15       27       76
12  18       31       81
13  21       35       86
14  24       39       91
15  27       43       96
16  30       47        1
17  33       51        6
18  36       55       11
19  39       59       16
20  42       63       21
21  45       67       26
jeff101's picture
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If the electron density (ED) were not periodic,
as might occur if the ED were only nonzero within a box covering
x=0-60, y=0-80, and z=0-100, for example,
there is another trick you can do with fminsearch
to control the size of the initial simplex, as below:

Say the protein's center starts at (x,y,z)=(40,60,20)
in the same coordinate system as the electron density.
If you feed these coordinates directly into fminsearch,
the initial simplex will be:

     actual
       xyz
(1) 40,60,20 & its score
(2) 42,60,20 & its score
(3) 40,63,20 & its score
(4) 40,60,21 & its score

If you instead shifted all coordinates by +100 units outside
of fminsearch and then shifted them back by -100 units before
evaluating their score, you'd get for the initial simplex:

      shifted     actual
        xyz         xyz
(1) 140,160,120  40,60,20 & its score
(2) 147,160,120  47,60,20 & its score
(3) 140,168,120  40,68,20 & its score
(4) 140,160,126  40,60,26 & its score

Next, if you shifted all coordinates by +400 units outside
of fminsearch and then shifted them back by -400 units before
evaluating their score, you'd get for the initial simplex:

      shifted     actual
        xyz         xyz
(1) 440,460,420  40,60,20 & its score
(2) 462,460,420  62,60,20 & its score (x goes outside 0-60 here, where ED is zero)
(3) 440,483,420  40,83,20 & its score (y goes outside 0-80 here, where ED is zero)
(4) 440,460,441  40,60,41 & its score

Finally, if you shifted all coordinates by -80 units outside
of fminsearch and then shifted them back by +80 units before
evaluating their score, you'd get for the initial simplex:

      shifted     actual
        xyz         xyz
(1) -40,-20,-60  40,60,20 & its score
(2) -42,-20,-60  38,60,20 & its score 
(3) -40,-21,-60  40,59,20 & its score 
(4) -40,-20,-63  40,60,17 & its score

As you can see, the size of the shift controls the size of the initial simplex,
and the sign of the shift controls which direction the simplex will explore.

jeff101's picture
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If you can get the "Center Protein on Density" button
to work better, perhaps as detailed above, it would
be nice if a player could select certain segments
first and then have the "Center Protein on Density"
button optimize the protein's position & orientation
as if the selected segments were the only scoring
segments for the entire protein. This way, if a player
was sure about the structure of a certain section
of the protein, say segments 1-20 and 45-90, he/she
could select just those segments, then press the
"Center Protein on Density" button to find the
position & orientation that gives the best score
for segments 1-20 and 45-90 only.

frood66's picture
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align protein to density has always been a waste of time - best it is removed as Flat was gonna do years ago. Best to ignore this option.

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