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.
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.
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 84 557 | Tue, 03/08/2016 - 22:13 | 2 comments )
Snowflake 2015/6 Puzzle Results!
We also have a student working with us decide this design from BCAA was his favorite.
Posted by inkycatz 84 1577 |
Thu, 01/14/2016 - 22:14 |
That wraps it up for this challenge - but we really appreciate all the effort put into the designs and hope you enjoyed the extra challenges from this year's "Snowflakes, Revisted".
Devprev Drug Design Update
I want to thank you for taking the time to test the first drug design puzzle. It is very nice to be part of a community that is so enthusiastic and helpful in tracking down bugs, reporting them, and improving science. I know that it can be extremely frustrating testing things that are broken or that do not perform in logical ways. Thank you for sticking it through and reporting the bugs and feature requests.
The idea behind releasing the puzzle to devprev without any information was to get a handle on what needed to be done to improve the drug design module without the constraint of a specific problem being solved. In the future, this will not be the case and a detailed description of the puzzle and the disease you are working on will be given.
This puzzle only featured one small aspect of the drug design tools and modes. In this puzzle, you were allowed to only change the atom identity to a Carbon or Nitrogen. By limiting the tools, we were able to identify specific problems with drug design mode (see below for summary). This is not what the future is of drug design. Adding large and small fragments, extending the small molecule by specific atoms, designing through synthetic rules, and queuing ligands are all tools that were not available. To let everyone get a peek at what is to come, jflat has created another sub group that has all the tools available. We are currently testing this build, but look for a blog post in the future where we will give you instructions on how to obtain it.
Here is a summary of the bugs/features that were reported.
We have tutorials! We just have not released the tutorials. The tutorials take you through a scientific paper where rational drug design was used to create an inhibitor for the FK506 binding protein. The tutorial puzzles will be in the new experimental drug design group that is being set up.
There were a lot of bugs/features about the ligand grids. A lot of people wanted the color of the grids to be changed. Is it better to have a simple color change is needed or the ability to change the color on the fly is needed?
The ligand grids were put in place to show contact points where you can design acceptors/donors atoms or fragments. Right now, the grids only show acceptors, donors, or repulsive scores. The future of the grids is to include information about structure activity relationships (SAR) of small molecules. SARs help identify regions of the small molecule or protein that like specific features, like hydrophobic/polar atoms, bulky/small fragments, etc. SARs are unique to each protein, so the ligand grids will change.
Finally, there were numerous bugs with the grids. The grids would disappear/appear randomly, or move, or not show when toggled and the slider was moved. These bugs will be fixed!
Ligand jumping out of pocket
I believe that I have tracked down the problem for this. Interestingly, I believe it is how I set up the ligand center filter, which was supposed to keep the ligand in the binding pocket. You have to love irony.
Where to begin? The idea for limiting wiggle, which is what the puzzle was supposed to do, is that drug design is usually done with a fixed backbone with no wiggles/shakes. While this is the general rule of thumb, there are optimization steps done to the backbone and sidechains throughout the design process. The problem with this specific puzzle, and why we wanted to limit wiggle/shake, is that the binding pocket was extracted from a larger protein. There were cutpoints at the end of each helix. Through internal testing, the protein would explode each time I wiggled the protein. I thought that I had fixed the issue, but it looks like there were some problems left.
For the future, the current plan is we will not limit wiggle or shaking. One of the goals of the Foldit community is to develop new strategies to fold proteins. For drug design, we want to keep in alignment with those goals and allow free thought and movement of the protein. New puzzles will not have these constraints associated with them (unless they are really needed).
One thing not shown in this puzzle is on the fly rotamer development. This means, each time you modify the ligand, a whole set of new rotamers are generated. This feature is enabled in the new experimental group.
Scoring is notoriously difficult for small molecule drug design. For this puzzle, we did not make any modifications to the score function to make it easy to distinguish which small molecule was the best. There is a new filter that we have developed that better recapitulates experimental values, but it was not included in the puzzle. Speaking of filters, there will be a whole lot of them introduced in the future!
We look forward to your additional feedback!( Posted by free_radical 84 1577 | Fri, 12/04/2015 - 17:49 | 0 comments )
Let's Get Ready for Drug Design Puzzles!
The first drug design puzzle is on its way! This will likely take place next week (unless of course, we run into currently unforeseen issues**).
I would like to first tell you why I am particularly excited about this series of puzzles. During the past decade, advances in drug design (specifically structure-based drug discovery) have seen a lot of success. However, the automated tools for this are encountering a huge problem with the total chemical space that can be sampled. It is estimated that the theoretical possible drug-like molecules is 1030-1060. This means that more than 99.9% of all drug-like molecules remain to be synthesized and explored for their therapeutic benefit. The scale is huge!
This is where you, as Foldit players, can help. The immense chemical and conformational space that needs to be sampled is greatly reduced with human spatial recognizing skills, which are far more robust at recognizing patterns than computer algorithms and can intuitively sample conformational and chemical space.
There is a lot of new technology involved with the drug design puzzles – it ranges from new drug design algorithms to robots! We will start covering these topics as the puzzles are introduced. For now, we are introducing a series of simple puzzles to help you understand some of the new tools. As time passes, we will release more complicated drug discovery problems and will start to provide targets with the hope of fighting a specific disease. The diseases that we will work on are rare and neglected diseases; these diseases have little research done on them and represent a space where the Foldit community can make a huge impact. If you have time, check this article out on the growing problem of rare and neglected diseases.
We look forward to hearing your feedback on these puzzles!
** which we did but we're ironing out!( Posted by free_radical 84 1577 | Tue, 09/29/2015 - 15:49 | 4 comments )
It’s almost time for class to be in session once more, and we want to welcome all our new students (academic and from the school of life) to Foldit! We have put together some handy tips to make your playtime in Foldit enjoyable.
Pick a good name but remember it is visible to everyone! Remember it should fit within the community guidelines, but more importantly, should reflect you - but not to the point where you’re using your email address as a login ID. That is just a bad idea for internet safety in general, so please don’t do this. Keep your name PG and something you’d be proud to see on top the leaderboards. If it’s too late and you think you've chosen badly with your username already - I can help you fix that. No judgement from me, we all veer off into “thought it was funny at the time” land on occasion.
Be patient! Foldit has an amazingly steep learning curve. A lot of our players are helpful, but being a global community, they may not always be watching the chat channel to answer questions. Have you checked our wiki? Did you try resetting, rereading the tutorial and trying again? Were you aware of the vast range of videos available you could watch? These are all great first steps but if they don’t get you what you need to know, then ask!
If you are having technical issues with a puzzle, please post them in the puzzle thread that goes with the puzzle you're having trouble with! This is the best way for our scientists and developers to find your issue. If you want to join in on some great learning threads, head to the forums!
We’re so glad you could join us and hope to see you around the community soon.( Posted by inkycatz 84 1577 | Fri, 09/04/2015 - 17:44 | 0 comments )