Sheets and Barrels

One of our players recently asked an interesting question in the Forum, about structural components that differentiate beta-sheets and beta-barrels. We posed this question to the Baker Lab's beta-barrel specialist Anastassia Vorobieva, and here's what she had to say...



Question, by brow42:
We recently had a design puzzle that preferred sheets. Some players made a sheet sandwich and some made beta barrel. We all made hydrophobic cores. But what structural component in real proteins lead to one or the other?


Answer, by bkoep:
I'm not the expert on this, but I can tell you what I do know. Perhaps I can track down another Baker lab scientist to follow up...

In many beta barrels, there are key positions that adopt irregular backbone conformations to reshape the beta sheet. Some positions adopt a "beta bulge," in which an extra residue is inserted between two residues of a beta strand. In the primary sequence, this residue would interrupt the normal pattern of alternating polar and nonpolar residues. There are also "glycine kink" positions, in which a glycine residue deforms the beta sheet by adopting a conformation unfavorable for other amino acids.

In beta sandwich proteins (and in many other structures with beta sheets), the "edge strands" of a beta sheet are often sprinkled with polar residues on the core-facing side of the sheet (which is normally nonpolar). Sometimes these are residues like TYR, which has a hydrophobic region that can contribute to core packing, as well as a polar atom that can extend out into solvent to make hydrogen bonds.


Complete answer, by Anastassia Vorobieva, PhD:
As bkoep pointed out, the presence of glycines in the middle of the beta-sheet (which is rare in beta-sandwiches), the position of the bulges and the presence of edge polar residues are good discrimination criteria between beta-sandwiches and beta-barrels.

kink.png

However, there is no easy answer and we still have no clear idea of how these structural elements interact with each other. For example, beta-bulges are present in both beta-sandwiches and beta-barrels. Only their position matters. And some beta-barrels have polar residues in their core, especially those that bind small molecules. And to make everything even more confusing, some beta-barrels are able to close without the presence of glycines in the sheet!

To get a little bit more into details, beta-strands like to have a right twist. In other words, the side chains and the hydrogen bonds tend to rotate clockwise along a beta-strand.

twist.png

This individual strands twist results in the "fan-shaped" beta-sheet mentioned by Susume. However, twist can be constraint in strands located in the middle of a sheet as such strands have to interact with the neighbor strands that have their own twist. In beta-barrels, the curvature necessary to close the barrel is hardly compatible with the individual twist of the beta-strands. As a result, there are some key positions in the barrel where the strand just can't continue to twist to the right and simultaneously interact with the two neighbor. There are several strategies in native proteins to "reset" the twist in such regions:
- Placing one glycine, which is the only residue that can twist to the left.
- Placing a bulge, which forces the right twist at the expense of the hydrogen bonds sometimes.
- Reduce the number of inter-strand hydrogen bonds. In the barrels that are able to close without glycines the strands typically interact with a larger offset.

To design beta-barrel proteins de novo, we are currently working on strategies to predict the key regions in the sheet were the twist will become a problem.

For your models in Foldit, here are some ideas to find twist problems:
- The side chains and the hydrogen bonds rotate to the right along the strand.
- If the twists of two neighbor strands are not coordinated, the side-chains of two interacting residues will tend to bend towards each-other. When two neighbor strands twists are well coordinated, the side-chains are parallel to each-other.
- The bending of the side-chains towards each-other is likely to cause several problems in the structure. These side-chains are likely to clash with each-other and the local torsion of the backbone to be unfavorable. As a consequence, the Foldit score will probably be negatively affected if one tries to force closure of a sheet that is more likely to fold into an open sandwich.

To summarize, the presence of glycines and polar edge-residues are good discriminators between barrels and sandwiches. If they are not sufficient, look for clashes and score problems that would indicate that you are trying to force the closure of a sheet that does not meant to be closed.

Regarding the loop length mentioned above, it should not have an influence in a properly twisting sheet, as the twist of the turn is compatible with the overall twist of the strand. However, spvincent is absolutely right in the case if the twist of the strands is not properly adjusted. Then the constraints building up by that unappropriated twist will be especially high in the loop region and a longer loop will help.

( Posted by  bkoep 73 727  |  Tue, 03/08/2016 - 22:13  |  2 comments )
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spvincent's picture
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Thanks for the post: does

Thanks for the post: does this mean that the current penalty for glycines in sheets in design puzzles needs to be rethought?

bkoep's picture
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Tough problem

In general, the problems associated with GLY in secondary structures are severe enough that we really want to avoid them, so the penalty is warranted. On the other hand, such a broad GLY penalty clearly prohibits anomalous cases, like this, in which a β-sheet GLY is important.

This is likely a problem we won't be able to address until we have a better understanding of beta barrels and other folds in which GLY is important to local secondary structure.

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