Copyright Kevin McGregor

Beta-Strand Shuffler

What is Beta-Strand Shuffler?

Beta-Strand Shuffler
The Beta-Strand Shuffler generates all N! * 2^(N-2) possible beta-sheet topologies. For each topology the program then proceeds to slide de strands relative to the others, this is called registering. Then, for each valid strand configuration the program evaluates the beta-sheet in a fashion similar to [3] (see MODEL section). This program is usefull to generate plausible beta-sheet topologies given a list of beta-strands. The list of strands can be inferred from secondary structure prediction or CD or NMR.

PROGRAM

The featured beta-sheet is from Baker's Top7 de novo protein (PDB code 1QYS) [12]. Step 4 is used to get the mean number of H-bonds per generated sheet, here 28, and is used in Step 5 with the -H and -B options. The minimum sheet energy should be -75.29 kcal/mol ("grep Total baker.sheet.top | sort -g"), and corresponds to the native topology in Top7. The O option specifies which residues should be on opposite sides of the sheet, so as to force the alpha-helices to go on top of the sheet. Residues 23 and 46, as well as 54 and 78, are forced to be on opposite sides of the sheet. The extent of the strands are those annotated by our program beta-Spider.

MODEL
The energy model that is used to score the beta-sheets is as follow:

Beta-Strand Shuffler Model
Note: I have derived the optimal weights for each terms in this equation and this is a subject to a paper. e-mail me for further details.

RESULTS
Following the execution of:

"./bShuffle.exe -S -R 6 -O 23-46 -O 54-78 -H -B 28 ./baker.str"
Energy of generated sheets
The best topology for Top7 given by bShuffle is:
 2 -> [ 15:K+][ 16:N ][ 17:F@][ 18:D-][ 19:Y@][ 20:T ][ 21:Y@][ 22:T ][ 23:V ]
 1 <- [ 12:D-][ 11:D-][ 10:I ][  9:N ][  8:V ][  7:Q ][  6:V ][  5:Q ][  4:I ]
 3 -> [ 46:K+][ 47:R+][ 48:V ][ 49:R+][ 50:I ][ 51:S ][ 52:I ][ 53:T ][ 54:A ]
 5 <- [ 94:L ][ 93:Q ][ 92:G ][ 91:E-][ 90:V ][ 89:T ][ 88:V ][ 87:T ][ 86:D-]
 4 ->         [ 78:D-][ 79:I ][ 80:N ][ 81:V ][ 82:T ][ 83:F@][ 84:D-]        
       Pairing Energy:  -25.50 kcal/mol
Hydrophobicity Energy:  -26.17 kcal/mol
	(Face 1 Hydrophobicity Score:  +17.32)
	(Face 2 Hydrophobicity Score:  -21.56)
     H-bonding Energy:  -20.00 kcal/mol
	(Alternative 1:  32 H-bonds  [ 54 with   4]  Energy: -10.00 kcal/mol)
	(Alternative 2:  36 H-bonds  [  4 with  23]  Energy: -20.00 kcal/mol)
---------------------------------------
   Total Sheet Energy:  -75.29 kcal/mol
Which also happens to be the native topology, and the resulting beta-sheet is in a pure anti-parallel configuration. The H-bonding network in the crystal file of Top7 (PDB code 1QYS) is such that residue 4 forms a closed ring with 23, which is the alternative that leads to the maximum number of H-bonds. But also notice that there are also other alternatives which are energetically "close", for example:
 3 -> [ 46:K+][ 47:R+][ 48:V ][ 49:R+][ 50:I ][ 51:S ][ 52:I ][ 53:T ][ 54:A ]
 1 <- [ 12:D-][ 11:D-][ 10:I ][  9:N ][  8:V ][  7:Q ][  6:V ][  5:Q ][  4:I ]
 2 -> [ 15:K+][ 16:N ][ 17:F@][ 18:D-][ 19:Y@][ 20:T ][ 21:Y@][ 22:T ][ 23:V ]
 5 <- [ 94:L ][ 93:Q ][ 92:G ][ 91:E-][ 90:V ][ 89:T ][ 88:V ][ 87:T ][ 86:D-]
 4 ->         [ 78:D-][ 79:I ][ 80:N ][ 81:V ][ 82:T ][ 83:F@][ 84:D-]        
       Pairing Energy:  -21.31 kcal/mol
Hydrophobicity Energy:  -26.17 kcal/mol
	(Face 1 Hydrophobicity Score:  +17.32)
	(Face 2 Hydrophobicity Score:  -21.56)
     H-bonding Energy:  -20.00 kcal/mol
	(Alternative 1:  32 H-bonds  [ 23 with   4]  Energy: -10.00 kcal/mol)
	(Alternative 2:  36 H-bonds  [  4 with  54]  Energy: -20.00 kcal/mol)
---------------------------------------
   Total Sheet Energy:  -71.84 kcal/mol
As you can notice, each of the sheets present the same amino-acids on the same faces; we cannot discard any of them based on the fact that a sheet has a less hydrophobic face. Also, each of these sheets can host as much as 36 H-bonds, so here too we cannot pick the best sheet based on the number of H-bonds. Interestingly, both topologies introduce a pair of networked salt bridges (15:K-12:D-46:K), which is electrostatically more stable than isolated salt bridges [6] (here the energy calculations do not account for this stabilizing effect). Also of interest is the fact that both topologies should prevent amyloid fibril formation by hosting an unpaired charged residue in their border strands [7]. However, the second alternative, even though it scores close to the first one, is such that the two alpha-helices are on opposite sides of the sheet, and thus one of them will be in contact with the less favoured 18:D-91:E unbalanced negative charges.

SOURCE CODE
You can grab the source code here:

Further instructions can be found in the main .C file. I would appreaciate to be informed of any source code modifications so I can merge them into the current sources and that everyone has the latest and best features.

Last source code update: 20/12/2004.

REFERENCES

CONTACT

Marc Parisien
Created: 26/10/2004 Last update: 22/11/2004
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