Foldit Newsletters

[agcohn821]

Newsletter August 27: Getting Edgy with Sheets

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 2031: IL-2R Binder Design with AlphaFold Predictions

Puzzle 2032: Symmetric Trimer Design with AlphaFold Predictions

Today’s Master Folding Tips

Let’s talk about sheets and strands! Although we usually use “sheets” to refer to any of the zigzag bits, the scientific term for what we usually think of as a sheet is a “strand,” and a “sheet” refers to the group of strands all hydrogen bonded together.

Now that we have that language, I can tell you more about edge strands. Foldit likes it when the strands on the edges of your sheets are blue hydrophilics. But in the real lab, those edges are too floppy without some sticky oranges to pull the edges into the core of the protein.

What can you do about this? Well, besides adding some oranges to your edge strands, you can also make the edge strands shorter. This makes them less likely to be floppy loops. You can also try adding a beta bulge — an extra residue in the normally alternating zigzag of a strand, which causes the strand to bulge a little. You can read more about beta bulges (and glycine kinks, which I haven’t mentioned) here, or on Wikipedia, or in the advanced section of my guide to Foldit. For the more expert folders, check out figure 3 of this paper! Thanks to veteran player and up-and-coming scientist Susume for all of these tips!

Are you interested in using Foldit for education? Tell us about it at mail.fold.it@gmail.com! We’re actively looking into ways to support education using Foldit!

Until next time, happy folding!

[agcohn821]

Newsletter September 3: Back to School with Foldit!

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 2034: TGF Receptor Binder Design with AlphaFold

Puzzle 2035: Symmetric Trimer Design with AlphaFold

Upcoming Updates

It’s September and you know what that means: time to head back to school! This back-to-school season, we’re integrating Educational Mode directly into the regular Foldit client! We’ve also made some big improvements to Educational Mode, including two brand new sets of puzzles: the Popular Proteins set lets you play with several of nature’s classics, including collagen, insulin, ubiquitin, and fibrin! The Bacteria and Viruses set challenges you to play with some of our most difficult puzzles over the years as we tackled Coronavirus, Ebola, the HIV protease, E. Coli, and the famous Mason-Pfizer Monkey Virus!

On top of that, here are some other minor features you can look forward to in the upcoming update:

• New camera features! Try pressing Shift+Home to make the camera rock back and forth gently, or Alt+Home to spin the camera around.
• Tooltips in the Campaign and Education puzzles now support going back to previous tooltips and quickly closing them out completely.
• You can now press Tab on a residue in the Campaign and Education puzzles to view additional information on that residue.

Are you an educator using Foldit in your classroom? Let us know, and give us feedback on how we’re doing! Email us at mail.fold.it@gmail.com to tell us how you’re using Foldit and what we can change to better suit your educational needs.

Today’s Master Folding Tips

Today we’re taking a closer look at the amino acids (AAs) in your toolbox: there are 20 of them and they each have unique properties for folding. For now, though, I’m going to simplify it a lot into their most common secondary structures.

For helixes, just remember MALEK: Methionine (M), Alanine (A), Leucine (L), Glutamate (E), and Lysine (K). Those are the AAs that love being in helixes.

For sheets, it’s less clear what to put, but we know that Isoleucine (I), Valine (V), and Glutamine (Q) do pretty well there.

For loops, your best bet is usually Glycine (G), Arginine (R), or Serine (S), although Threonine (T) likes sitting next to Serines if you have one.

Next week, we’ll continue our close look at some more AAs and their properties

Reading this newsletter on the forums? Sign up here to get them delivered straight to your email a few days earlier!

Until next time, happy folding!

[agcohn821]

September 10: Check Out Those Bonds!

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 2037: Cortisol Ligand Binder Design with AlphaFold Predictions

Puzzle 2038: Symmetric Tetramer Design with AlphaFold Predictions

Take a close look at that hydrogen bond network! That’s all arginine and glutamate putting in some serious work! We’ll dive more into them in today’s tips.

Upcoming Updates

Here’s what the dev team has been working on recently!

• A new-and-improved interface for getting predictions from AlphaFold
• New features to help with Electron Density puzzles

We also have a few projects in the pipeline for some bigger changes to the interface, but we’ll talk more about that later!

Today’s Master Folding Tips

Today we’re continuing our exploration of the 20 amino acids in your toolkit! Starting with…

Alanine: swap this little guy in anywhere, he’ll fit in any SS!

Arginine: this hydrophilic has a lot of rotamers, or ways it can be rotated, so put it anywhere on the outside of your protein and shake it out!

Asparagine: This sidechain makes good hydrogen bonds with the backbone, so it’s useful at the edges of helices and when your sheets are turning.

Aspartate: Do not put this one in helices!

Cysteine: If you can get two cysteines together, they form a disulfide bridge, which is more powerful than a hydrogen bond! Use a pair of these at right angles when you need a really strong bond.

Glutamine: This long hydrophilic is good at stabilizing helices and sheets, but less good at being flexible. Keep it out of loops.

Glutamate: This one is best for helices and hydrogen bonds.

Glycine: The most flexible amino acid of them all, it’s best for loops (especially U-turns) and terrible at stabilizing helices and sheets. If a residue is having trouble bending, put a glycine next to it to take some of the load off.

Well! I think that’s enough for today. Ready to try your hand at designing with these amino acids? Try Puzzle 2041: Symmetric Tetramer Design with AlphaFold Predictions now!

Until next time, happy folding!

[agcohn821]

Newsletter September 17: Pumpkin Pi Stacking

Hey folders!

Dev Josh here with your weekly Foldit update. Today’s theme is pi stacking. And because it's fall, it's time for pumpkin pi stacking! Read more about pi stacks here. In the meantime, enjoy this visual pun:

Solutions from This Week's Puzzles

(Disclaimer: This is not scientific feedback; these solutions are not officially endorsed by the Foldit scientists.)

Puzzle 2040: IL-2R Binder Design with AlphaFold Predictions

Puzzle 2041: Symmetric Tetramer Design with AlphaFold Predictions

Today’s Master Folding Tips

This week we’re continuing our deep dive into the amino acids and how to use them. Let’s jump back into it:

Histidine: This hydrophilic has both a donor and an acceptor. That, plus its uniquely pentagonal aromatic ring makes it a versatile sidechain. Despite its hydrophilicity, you can use it for pi stacking! Try stacking it with other histidines or with the hydrophobic aromatics.

Isoleucine: This AA is a fan-favorite for sheets and terrible in helices! Fill your sheets with isoleucine to start with, and mutate in some valines, leucines, and methionines as needed.

Leucine: Despite being similar in shape and function to isoleucine and valine, this branched-chain AA is different enough that it prefers helices over sheets, but keep it in the hydrophobic core!

Lysine: This long AA has two great purposes: (1) forming hydrogen bonds, especially with negatively charged AAs like Aspartate, and (2) stabilizing helices. Keep in mind, though, that its long carbon chain is hydrophobic: in the ideal case, only the charged end is sticking out of the protein.

Methionine: This hydrophobic does wonders for stabilizing a helix, but it still wants to be in the hydrophobic core if it can be. Although it has a sulfur, Methionine is pretty non-reactive and can’t form disulfide bridges like cysteine can.

Phenylalanine: Also known as the queen of pi stacking. If you need your pi stack to hydrogen bond as well, swap in a tyrosine instead. Otherwise, keep the phenylalanine to avoid BUNS.

What an info dump! Take a week to absorb this, and I’ll be back again next Friday with more tips on using your AAs to the best of their abilities!

Until next time, happy folding!

[agcohn821]

Newsletter September 24: PST, Here's How To Turn

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 2043: CD47 Binder Design

Puzzle 2044: Symmetric Tetramer Design with AlphaFold Predictions

Today’s Master Folding Tips

This week, we’re wrapping up our review of the amino acids in detail!

Proline: Master of bending, this amino acid has a niche purpose but excels at that one thing. Use it to link strands together in a sheet or put it in the first turn of a helix to help the helix get started, but never put it in the middle of helices or sheets.

Serine: Because of its small size, serine is often useful in loops and less useful in helices. Serine is often found next to Threonine forming ST motifs and ST turns.

Threonine: Serine’s buddy for ST motifs and ST turns. Put it in loops. The two of them are also useful for making hydrogen bonds.

Tryptophan: Hoo boy. This guy is large. Literally the largest amino acid of them all, and the only amino acid with two rings. Tryptophan is useful for pi stacking and filling up space in the hydrophobic core.

Tyrosine: Like phenylalanine, tyrosine can be used for pi stacking. But unlike phenylalanine, it has an oxygen hybrid acceptor/donor, making it great when you want to pi stack but also need to satisfy a buried unsatisfied polar atom in that space.

Valine: Like its cousins isoleucine and leucine, Valine is most common in sheets and terrible in helices because it’s C-beta branched and bulky.

Want to see what a great design looks like? Check out September’s Design of the Month by spvincent and ichwilldiesennamen!

Until next time, happy folding!

[agcohn821]

Newsletter October 1: The No BUNS Challenge

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 2046: TGF Receptor Binder Design

Puzzle 2047: Symmetric Tetramer Design with AlphaFold Predictions

The No BUNS Challenge

Looking to push your Foldit game to the next level? This month, try our No BUNS Challenge! On any design puzzle, create a solution with absolutely zero* buried unsatisfied polar atoms (BUNS) and share it with scientists with the tag “NO BUNS” to receive a special role on our Discord server! Good luck, BUNS-fighters!

*Some puzzles may have existing BUNS that are impossible to satisfy. Players will win the challenge for submitting a solution with the minimum possible number of BUNS per puzzle.

Today’s Master Folding Tips

Here are some tips for finding and satisfying BUNS:

Turn on “Show bondable atoms” to light up your fold like a jigsaw puzzle of connect-the-dots

Show hydrogens (“Show Bondable H”) for an even clearer picture of potential bonding. You can also see this gallery and this table for more details on which amino acids can form what bonds.

Struggling to get a sidechain in the right rotation to form a bond? Use the Pick sidechains tool to cycle through rotamers.

Want to get these newsletters directly in your email as soon as they go out? Click here to sign-up and get your weekly Foldit news and tips every Friday!

Until next time, happy folding!

[agcohn821]

Newsletter October 1: The No BUNS Challenge

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 2046: TGF Receptor Binder Design

Puzzle 2047: Symmetric Tetramer Design with AlphaFold Predictions

The No BUNS Challenge

Looking to push your Foldit game to the next level? This month, try our No BUNS Challenge! On any design puzzle, create a solution with absolutely zero* buried unsatisfied polar atoms (BUNS) and share it with scientists with the tag “NO BUNS” to receive a special role on our Discord server! Good luck, BUNS-fighters!

*Some puzzles may have existing BUNS that are impossible to satisfy. Players will win the challenge for submitting a solution with the minimum possible number of BUNS per puzzle.

Today’s Master Folding Tips

Here are some tips for finding and satisfying BUNS:

• Turn on “Show bondable atoms” to light up your fold like a jigsaw puzzle of connect-the-dots
• Show hydrogens (“Show Bondable H”) for an even clearer picture of potential bonding. You can also see this gallery and this table for more details on which amino acids can form what bonds.
• Struggling to get a sidechain in the right rotation to form a bond? Use the Pick sidechains tool to cycle through rotamers.
Want to get these newsletters directly in your email as soon as they go out? Click here to sign-up and get your weekly Foldit news and tips every Friday! Until next time, happy folding!

[agcohn821]

Newsletter October 8: The Pattern Language of Foldit

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 2049: CD47 Binder Design

Puzzle 2050: Symmetric D2 Tetramer Design with AlphaFold Predictions

In Case You Missed It

Want to know more about interpreting AlphaFold structures? Check out this video. Thanks Susume for finding it!

The No BUNS Challenge

Congratulations to this week’s winners!

• nspc
• sgeldhof
• HuubR

The challenge will continue through the rest of October, so if you’d like to earn a special Discord role, submit a design solution with the tag “NO BUNS” using the Share with Scientists button.

Today’s Master Folding Tips

I’ve been thinking a lot about design patterns lately. Architecture has patterns to how buildings and urban spaces get designed. So do game design and game programming. But protein design also has design patterns. They’re called motifs, and they’re a big part of bottom-up design. In fact, here’s a whole glossary of protein design motifs. Good design, I’ve learned, is about having a library of references and experiences to draw from. Motifs are good tools to have in your toolkit.

Until next time, happy folding!

[agcohn821]

Newsletter October 15: The Shake-Wiggle Jiggle

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 2052: IL-2R Binder Design

Puzzle 2053: Symmetric Trimer Design with AlphaFold Predictions

The No BUNS Challenge

Congratulations to this week’s winner: silent gene!

The challenge will continue through the rest of October, so if you’d like to earn a special Discord role, submit a design solution with the tag “NO BUNS” using the Share with Scientists button.

Today’s Master Folding Tips

Let’s talk stabilization. When you want to stabilize your fold, you use shake, wiggle, and clashing importance, right? But in what combination? Generally, you want to start at a low (but non-zero) clashing importance and work your way up to 1.0. Lowering the CI helps your fold pack in well, but lowering it to zero would just make it collapse in on itself. Once your CI is low (around 0.1 or so), give the fold a shake so that the orange sidechains can pull themselves into the core. Then you can wiggle so the backbone can adjust itself, slowly increasing the CI as the protein stabilizes. Sometimes, you might need to go back and forth with shake and wiggle, but usually you want to shake at a low CI so that the sidechains pack in as much as possible. It’s easier to expand a protein than condense it, so start your fold tight and let it relax out.

Want to get the latest Foldit features before everyone else? Check out our devprev update group!

Until next time, happy folding!

[agcohn821]

October 22: Stick It To Those Sheets!

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 2055: CD47 Binder Design

Puzzle 2056: Symmetric Trimer Design with AlphaFold Predictions

Recipe of the Week

When you’re looking to mutate just the interface for a binder design, check out nspc’s mutate interface!

Today’s Master Folding Tips

Having trouble banding sheets together? Turn on stick view! In stick view (with “show bondable H” on), you can more clearly see the hydrogens and hydrogen acceptors: band directly from the hydrogen to its acceptor for great results. Hydrogen bonds form when the hydrogen and its acceptor are around 2 angstroms apart, so set your band length somewhere between 1.75 and 2. Don’t be startled when you switch back to cartoon view and your bands look like they’re in a different place, they’re still where you placed them but they look different in cartoon view.

There’s still one week left in our No BUNS challenge! Submit a design solution with the tag “NO BUNS” using the Share with Scientists button to earn a special Discord role!

Until next time, happy folding!