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This is the place where we will describe some of the outcomes and results of your folding work, provide a glimpse of future challenges and developments, and in general give you a better sense of where we are and where foldit hopes to go in the future.

Welcome Students!

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!

Check out the FAQ, it's pretty useful.

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 79 2258  |  Fri, 09/04/2015 - 17:44  |  0 comments )

Drug design puzzles coming your way!

Hi everyone,

One of the problems that drug designers face seems innocuous at first: what would happen if a single atom in the small molecule changed from a carbon to a nitrogen or vice versa? Will this make the drug bind better to my protein target? At first glance, if you just look at the properties of the elements it might seem like an easy solution. Carbon in small molecules is mostly inert and “hydrophobic” while nitrogen is a “polar” atom and can either accept or donate hydrogen bonds. If a crystal structure is available, drug designers will replace a carbon with a nitrogen to form a hydrogen bond, which should increase activity. However, this can cause a conformational change in the ligand and reduce binding or the chemical properties change in such a way that it is hard to predict.

As you start to embark on your on drug designs for protein targets, you will be faced with a similar challenge. To this end, we have created a dataset of crystal structures with small molecules bound that have a single atom change, a carbon to a nitrogen or a nitrogen to a carbon. As your first drug design puzzle, you will be tasked to determine at which positions to change in order to increase binding to the target. To add on to the excitement, we have given the exact same dataset to our drug designers. At the end of the series of puzzles, we will post the results to see who did better!

Since these will be the initial drug design puzzles, we are looking for a lot of feedback. Functionality is limited in these puzzles (don’t worry, we will give you many more tools in the future and new gameplay modes!) in order to do a thorough testing of the interface. If we can, we will implement the requests that you make.
What is coming in the future?

New tutorials: Follow the steps of a group of scientist as they developed a new small molecule
New gameplay modes: Free design and synthesis based design
New media: chats with scientists and thoughts on the future of drug design

Questions? Add them here and we'll keep them in mind to answer in future posts!

( Posted by  free_radical 79 2258  |  Wed, 07/22/2015 - 15:39  |  2 comments )

Feedback on Marburg puzzle 1108 ("Compact 37-Residue Marburg Virus Inhibitor Design")

Hi, folks. Thanks to all who played the latest Marburg puzzle. We have looked over the results, and it looks like the scoring was promoting some of what we wanted to see, though I think that maybe we should have given a bigger bonus for creating a core (and maybe required a few more residues in the core). While the top-scoring designs looked pretty good, some of the most interesting were, once again, in the "shared with scientist" category. Two in particular stood out:

Susume of Anthropic Dreams created a very interesting-looking sandwich of beta-strands, with a great "leapfrog" arrangement of disulfide bonds (cys3-cys21, cys7-cys33). Importantly, all strands contributed hydrophobic residues to the core, and there were no voids in the core, so it's a plausible-looking fold for presenting the antibody loop. My one criticism is that this only makes one additional charge-charge interaction with the target and one additional hydrophobic interaction, but on the other hand, putting the effort into having a nice, stable fold might be a good strategy.

Design by Susme of Anthropic Dreams.

LociOiling from the Beta Folders went with a nice, classic helix packing against a three-stranded sheet. The helix is very nice and plausible, with one clearly hydrophobic face in which every turn either presents a hydrophobic amino acid residue, or is involved in a disulfide bond. Again, we have a nice "leapfrog" disulfide pattern of the sort often seen in small peptides in the natural world. In this case, my only criticism is that the third strand isn't doing much to contribute to the fold or to binding (with the exception of a single valine that's making a hydrophobic interaction with the target). Still, it's conceivable that this would bind just fine if it were truncated down to a helix and a two-stranded sheet...

Design by LociOiling of the Beta Folders.

...Which is a good segue into our next puzzle: a smaller, 25-residue Marburg binder. Why smaller? Stay tuned for the new puzzle for more information!

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( Posted by  v_mulligan 79 2258  |  Fri, 07/10/2015 - 05:20  |  5 comments )

Feedback on the last Marburg design puzzle

Happy Canada Day to our Canadian players!

We're about to give you a Marburg design puzzle, but I first wanted to provide a little bit of feedback on the last Marburg puzzle that we ran (puzzle 1073: Marburg Binder Design with Disulfides). We got some pretty good-looking designs back, but curiously, all of the best designs were ones that were shared with us using the "Share with Scientists" feature; they were not the top-scoring designs. This reflects one of the big challenges, for us, in giving these puzzles to the Foldit community: it's hard for us to figure out how to translate our qualitative idea of what a "good" design will look like into a set of quantitative rules that allow a computer to assign a higher score to a better design, and we didn't quite get it right on that puzzle.

We're going to revisit the 37-residue Marburg binder design in the new puzzle, but this time, we'll tweak the scoring and the filters to try to promote the features that we want to see. In particular, we'd like to see:

-- Compactness. Our favourite designs were the ones that were not so elongated. It's good to try to imagine how the peptide would look in the absence of the Marburg glycoprotein. If its structure depends on its interaction with the glycoprotein, and if it's floppy and unstructured in isolation, this means that the binding event must confer order on the peptide. This is entropically unfavourable (it's hard to increase the order of a physical system), and the price of ordering the peptide must be paid by a reduction in binding affinity. So nice, compact peptides that are likely to retain their structure in isolation are best for binding. We'll be including a core existence filter in the new puzzle to help to promote this.
-- Long-range disulfides. Disulfide bonds are a great way of enforcing order in a peptide, but this only works if they're holding together parts that would otherwise be inclined to move apart. A disulfide between two amino acids that are close together in linear sequence doesn't do a whole lot. Often, the best disulfide-bonding patterns (and the ones frequently seen in structured natural peptides) are "leapfrog" patterns. For example, you might link residue 1 to residue 20, and residue 10 to residue 30. This maximizes the linear separation between disulfide-bonded cysteine residues while minimizing the length of stretches of amino acids that contain no disulfide.
-- Lots of secondary structure. Many of the best designs had at least one helix lying across a sheet of at least two strands.
-- Lots of proline residues and few glycine residues. Proline helps to rigidify a peptide in a desired conformation. Glycine, on the other hand, is too flexible, and increases the number of possible alternative conformations, making folding into a single unique conformation more difficult. Although glycine is sometimes necessary (there are sometimes loops in which one residue has to be in an unusual conformation that no other amino acid type could access), we'd like to see few glycine residues if possible. In the new puzzle, we'll be increasing the penalty for glycine and increasing the bonus for proline.
-- Void-free packing. We recommend turning on the cavity or void display in the view options. This draws red spheres wherever there is an empty space in the core of the peptide being designed or at the interface with the Marburg glycoprotein. These red spheres are bad -- there shouldn't be empty spaces! If you can eliminate them, please do so (you should find that it helps your score, too).
-- Additional interactions with the glycoprotein. Although much of the interaction with the glycoprotein comes from the loop taken from the antibody crystal structure, the peptide is likely to have more affinity and specificity for its target if you can design additional interactions with the surface of the glycoprotein. Shape and charge complementarity beyond the antibody loop are good things! Now, this comes with a caveat: don't go for additional interactions at the expense of ordered structure. A peptide that lies entirely along the glycoprotein surface, forming lots of interactions with the surface and no interactions with itself, is likely to be too disordered to bind. If you can design in additional interactions with the surface that come off of well-ordered secondary structure elements that pack well with the rest of the peptide, though, that would be terrific.

Here are some of the solutions that we particularly liked:

retiredmichael of the Beta Folders had a nice design in which an alpha helix lies across one face of a three-stranded beta-sheet. This design had lots of secondary structure, a pretty good hydrophobic core (in which most of the secondary structure elements contribute), a nice disulfide bonding pattern, and relatively few voids in the interior of the peptide. The only criticism I'd have of this design is that one strand in the sheet does not contribute to the hydrophobic core; aside from this, this design looks very good.
Design by retiredmichael of the Beta Folders.

mimi of the Contenders created a very interesting topology with helices sandwiching a three-stranded beta-sheet. This creates a lot of opportunities for interaction with the surface of the Marburg glycoprotein. The one thing to watch out for, here, is that this design has a bit less of a hydrophobic core, which might hinder its folding.
Design by mimi of the Contenders.

MurloW of Anthropic Dreams made a design with a topology somewhat similar to retiredmichael's, albeit with the helix in a different orientation and a fourth strand on the beta-sheet. This also opens up possibilities for interactions with the glycoprotein -- but be careful about those voids at the interface!
Design by MurloW of Anthropic Dreams.

eusair's design put the helix on the opposite face of the beta-sheet to that chosen by retiredmichael or MurloW, and this allowed eusair to stick a valine very nicely into a cleft created by two prolines on the glycoprotein surface. I like this design quite a bit -- but be careful about those edge strands, that don't always contribute to the hydrophobic core.
Design by eusair.

Congratulations to all of these players, and good luck to everyone on the next puzzle!

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( Posted by  v_mulligan 79 2258  |  Wed, 07/01/2015 - 17:46  |  6 comments )

Your handy guide to Marburg, Ebola, and Foldit

We're revisiting Ebola and the Marburg virus with an upcoming series of puzzles! The team has indicated we'll be starting with some Marburg puzzles, although it is highly likely more Ebola puzzles will also appear.

Marburg virus disease (MVD) (formerly known as Marburg haemorrhagic fever) is a severe and highly fatal disease caused by a virus from the same family as the one that causes Ebola virus disease.

Find out what's going on lately with these puzzles and posts:
Mutate and Marburg, started by Susume

With that in mind and to get everyone back up to speed on this topic, we've compiled some of our previous efforts in this area. Feel free to check out our blogs:
Feedback on the last Marburg design puzzle (1073)
Review our blog post, talking about Puzzle 1000
Continuing the battle against Ebola

As well as check out previous related puzzles:
1144: How low can you go? 10-residue Marburg binder design
1117: Ultra-compact 17-residue Marburg virus inhibitor
1112: Compact 25-residue Marburg virus inhibitor
1108: Compact 37-Residue Marburg Virus Inhibitor Design
1073: Marburg Binder Design with Disulfides
1000: Breach Ebola's Defences!
975: Ebola glycoprotein 30-residue inhibitory peptide design
971c: Ebola glycoprotein peptide inhibitor design
884b: 74 Residue Ebola Binder Design
879: Ebola Binder Design with Disulfides
846: Ebola hotspot discovery

For more reading, when we were running frequent puzzles of these types before, spmm noted that Science/AAAS has a suite of free Ebola articles which are interesting, reasonably easy to read, and also have links to more complex papers and articles.

Additional information:
World Health Organization Ebola portal
The Mayo Clinic

As always, the Foldit team remains committed to research in this area and appreciates everyone's assistance on these puzzles!

( Posted by inkycatz 79 2258  |  Tue, 06/30/2015 - 22:01  |  1 comment )
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