Newsletter October 29: Let’s Look Longingly at Ligands
Hey folders!
Dev Josh here with your weekly Foldit update.
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2058: TGF Receptor Binder Design
Puzzle 2059: VHL Ligand Design
In Case You Missed It
Foldit has released a new Small Molecule Design Tool to accompany the PROTAC small molecule design project.
Today’s Master Folding Tips
This week, we’re all about ligands and small molecules. In a sense, ligand design is all about Foldit fundamentals: pack things together close, but not so close that they clash. Don’t leave any voids, and make sure every acceptor and donor is part of a hydrogen bond. It’s like a jigsaw puzzle where you get to decide the pieces. For the expert designers out there, check out this article on ligand design.
Try out the new tools today in Puzzle 2062: VHL Ligand Design Round 2!
Until next time, happy folding!
Newsletter November 5: A Blueprint for Success
Hey folders!
Dev Josh here with your weekly Foldit update.
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2061: Symmetric Trimer Design with AlphaFold Predictions
Puzzle 2062: VHL Ligand Design: Round 2
Today’s Master Folding Tips
Let’s talk about blueprints. If you’re not using the blueprint tool, you should be. Blueprints help you easily sketch out a first draft of a protein and keep your loops ideal, following the Koga & Koga design principles. Here are some of my favorite blueprint blocks:
- For sheet-to-sheet connections, try the yellow-red loop (including the ends the block shows blue-yellow-red-blue). Yellow-red is good for making a sheet and keeping it flat. If you want your sheets a bit more curved, use the green-green loop instead.
- For helix-to-helix connections, I recommend the green-blue loop (or red-green-blue-red with the helix ends) for 3-helix bundles. This loop is more common in nature, although you can also use the blue-red-blue loop if you need an extra segment in your loop. For 4-helix bundles, try the green-blue-blue loop because it has a shallower angle. When you’re putting your helices in a binder pocket or making space for a ligand, use the blue or blue-blue loops to angle the helices away and create a space in the middle. Blue-blue in particular is a very wide, almost horizontal angle.
Next week, we’ll cover helix-to-sheet and sheet-to-helix loops!
What are your favorite blueprint blocks? Let me know in the Discord or on the forums!
Until next time, happy folding!
Newsletter November 12: From Sheet To Helix And Back
Hey folders!
Dev Josh here with your weekly Foldit update.
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2063: Revisiting Monocyte
Puzzle 2065: Symmetric Trimer Design with AlphaFold Predictions
Today’s Master Folding Tips
This week we’re continuing our tips on using the blueprint tool to make ideal loops.
- For sheet-to-helix connections, try red-blue (or blue-red-blue-red including the ends) when you have longer helices. This loop works best when your helix length is twice the length of your sheet plus four (for example, with 7-residue strands, use an 18-residue helix) because the outward angle affords longer helices. If you have shorter helices, use the green-blue-blue loop; it points more at a downward angle so you don’t need the helix to be as long to line up with your sheet. Helices in this setup don’t need the extra four residues, so you could use a 14-residue helix for 7-residue strands. Be careful using the blue-blue-blue loop, its angle varies widely in nature so this loop is incredibly unpredictable.
- For helix-to-sheet connections, the big difference is the number of residues in the loop and whether it angles the sheet toward or away from the helix. Green-blue is a 2-residue loop that points away from the helix; green-blue-red is a 3-residue loop that also points away from the helix; and blue-red-red is a 3-residue loop that points toward the helix. Alternatively, you can think of blue-red-red as a blue-red-red-blue loop, including the first residue of the sheet, which makes it a 4-residue loop that points away from the helix, keeping all three of these loops consistent. In that case, the only difference here is how many residues you need in your loop, and it makes the choice simple.
There’s one blueprint loop I didn’t mention: the blue-red helix-sheet loop. Do you use this loop? Let me know on the Discord when you use it and why!
Until next time, happy folding!
Newsletter November 19: Check your fold before you wreck your fold!
Hey folders!
Dev Josh here with your weekly Foldit update.
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2067: TGF Receptor Binder Design
Puzzle 2068: VHL Ligand Design
Recipe of the Week
If you like to start your symmetric designs by pulling your monomer away from the copies and working on that first, you know how frustrating it can be to find them again. That’s why Bruno Kestemont wrote FindThem, a quick little recipe that helps you pull your symmetric copies back together again and get them in view. Thanks Bruno!
Today’s Master Folding Tips
On puzzles that have AlphaFold predictions, use it early and often to avoid “drilling” into a solution. Sometimes on binder design puzzles, you can make a mutation to your binder that makes it stick better to the target and gives you a better score, but that mutation might make the binder fold up worse on its own. And when scientists try to synthesize your design in the lab, they need it to fold up by itself!
AlphaFold helps because it only predicts how your binder will fold, it doesn’t look at the target. So while you’re working on attaching your binder to the target, keep checking with AlphaFold to make sure your confidence stays high!
Lastly, here’s a pro-tip from nspc: work from the prediction AlphaFold gives you, otherwise AlphaFold’s confidence score might not be reflecting the design you intended to make. This also makes it easier to see changes to the prediction over time as you make mutations.
New to Foldit? Say hi on our Discord! We love new players and we’re always happy to answer questions.
Until next time, happy folding!
Newsletter November 26: Thanks for playing
Hey folders!
Dev Josh here with your weekly Foldit update.
Today is Native American Heritage Day in the U.S., and I’m writing to you from the land of the Oneida people. If you are in the Americas, I encourage you to take a minute today to learn a bit about the indiginous peoples who first lived on these beautiful lands. Yesterday was also Thanksgiving in the U.S., and I am thankful that I get to spend time every week with the Foldit community. All of you are so dedicated to helping science through the puzzles we give you, and every time we are surprised by your ingenuity. So thank you, thank you for playing.
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2070: Symmetric Tetramer Design with AlphaFold Predictions
Puzzle 2071: VHL Ligand Design
Today’s Master Folding Tips
Foldit can be fun, but don’t forget to take breaks! It’s good for your body to change positions or stretch every 20 minutes. Check this link for more tips on ergonomic computer usage!
Take it easy this week, folders. Be kind to yourselves, you deserve it.
Until next time, happy folding!
Newsletter December 3: Haven’t a Clue-a About Lua?
Hey folders!
Dev Josh here with your weekly Foldit update. Happy Hanukkah to those who celebrate!
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2073: Olivetolic Acid Ligand Binder Design
Puzzle 2075: Virus Protein
Today’s Master Folding Tips
Lua is the programming language Foldit uses for recipes, also known as scripts and macros. If you’re looking to get into recipe-writing, here’s a guide for getting started with Lua. If programming isn’t your thing, maybe browse the recipes made by other players!
What do you think of our new interface? Let us know in our feedback section!
Until next time, happy folding!
Newsletter December 10: You Can Pick Your Friends, And You Can Pick Your Sidechains...
Hey folders!
Dev Josh here with your weekly Foldit update.
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2074: VHL Ligand Design
Puzzle 2076: Symmetric Tetramer Design with AlphaFold Predictions
Today’s Master Folding Tips
When you want to get a sidechain into position, don’t pull — pick! Use the Pick Sidechains tool to see all of the possible rotations for a sidechain and pick the best one. The tool even shows you how common each rotation is in nature — the more blue filled in the bar next to each rotation (or rotamer), the more common it is. Picking is a much more reliable way to get the sidechain where you want, so pick away!
Join a group to evolve other players’ work. You can even pick your friends’ sidechains!
Until next time, happy folding!
Boletín Informativo Diciembre 17: ¡Bienvenidos a Todos!
Hola plegadores!
Desarrollador Josh aquí con tu actualización de Foldit de la semana. Esta semana vimos muchas, muchas personas nuevas intentando Foldit desde muchos países diferentes, incluyendo México, España, Chile, República Dominicana y más. Pensamos que tenemos este video para agradecer. Estamos muy emocionados de tener a ustedes jugando. ¿Quiere saber dónde comenzar? Considere esta página que escribí para dar un guía de Foldit. O visite nuestra wiki aquí.
¡Buena suerte y diviértase!
Las Soluciones de los Rompecabezas de Esta Semana
(Descargo de responsabilidad: esto no es un comentario científico; estas soluciones no cuentan con el respaldo oficial de los científicos de Foldit.)
Rompecabezas
2078: Diseño Aglutinante del CD47
Rompecabezas
2079: Diseño del Ligando VHL
Consejos Maestros de Plegado de Hoy
Una de las mejores herramientas para el diseño es la herramienta Blueprint. Arrastre y suelte las piezas para hacer bucles fácilmente y dibuje sus hélices y láminas. Si usted es nuevo, intente usarlo para hacer un paquete de tres hélices. O experimente con una variedad de láminas y hélices. ¡Juntos encontraremos algo que funcione!
(One of the best tools for design is the Blueprint tool. Drag and drop the pieces to make loops easily and draft your helices and sheets. If you’re new, try using it to make a three-helix bundle. Or experiment with a variety of sheets and helices. Together we will find something that works!)
¡Venga y únase a nuestro Discord y hable en su idioma nativo en el canal #español! También me puede escribir personalmente si tiene preguntas, me encanta practicar mi español.
¡Hasta la próxima, feliz plegado!
Newsletter December 24: Merry Christmas
Hey folders!
Dev Josh here with your weekly Foldit update. If you celebrate Christmas, Merry Christmas!
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2081: Olivetolic Acid Ligand Binder Design
Puzzle 2082: VHL Ligand Design
Today’s Master Folding Tips
Here are three great ways to improve your folding:
-
Ask - When you don’t understand something in Foldit, get curious! You can ask in the chat, or on our forums, or check the wiki! Sometimes even Wikipedia will have the answers you’re looking for. From very beginner questions like what’s a sidechain to expert questions about chirality, the internet has the answers!
-
Share - One of the best ways to learn is to share. Share your screenshots and ideas in the chat, or on our Discord, and get feedback from other players on your designs!
-
Critique - The reverse of sharing is critiquing what other players share. What constructive feedback can you give them? And, if you don’t understand something enough to critique it, go back to step 1 and get curious!
Do you have insights to share about Foldit? Contribute to our wiki!
Until next time, happy folding!
Newsletter December 31: ...And a Happy New Year!
Hey folders!
Dev Josh here with your weekly Foldit update. Happy New Year! As we enter into 2022, here are some things to look forward to in the new year:
- A completely new website! Although this has been delayed some while we polish it up, it’s really nearly ready now! And the extra time has allowed us to build some really cool features for it.
- New Campaign levels! The Campaign as we know it will be getting a major overhaul.
- New Trim tool! Haven’t heard? Check out the sneak preview here!
- And more! But that’s all I’ll say for now ;)
Solutions from This Week's Puzzles
(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)
Puzzle 2084: Symmetric Tetramer Design with AlphaFold Predictions
Puzzle 2085: VHL Ligand Design
Today’s Master Folding Tips
When I first started folding, I was scared of designing from a blank slate: I didn’t know what to do with an extended chain of nothing but isoleucines. So here’s what you do, in 5 simple steps:
- Use the Blueprint tool to assign some helices and/or sheets. For example, if you want to make a triple helix, assign three sections to helices separated by a few segments of loops.
- Use Idealize SS on your secondary structures to make them into the helical and zig zag shapes you know and love.
- Use the Blueprint tool to add Blueprint blocks between the secondary structures as your loops. This will help keep your loops ideal, and should automatically bend your protein into the shape you’re thinking of. If it doesn’t, try another Blueprint block.
- Mutate the protein to turn those isoleucines into amino acids that better fit your fold.
- Stabilize your fold with a combination of shake and wiggle. Start at a low clashing importance, otherwise wiggle could make everything fly apart, then gradually bring the clashing importance up while alternating between shake and wiggle.
That’s it! After those five steps, you’ve got a protein design! Of course, there’s plenty more to do from there: attaching to a target for binder puzzles, or to symmetric copies for symmetry puzzles, or otherwise improving your fold and satisfying objectives. But those five steps will get you out of the blank slate rut!
Into streaming? Stream Foldit and let us know on the Discord! Your VOD might make it into this newsletter!
Until next time, happy folding!
