2 replies [Last post]
agcohn821's picture
User offline. Last seen 14 hours 18 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff


How to Foldit, Part 1: What’s a Protein?

Hey folders!
Dev Josh here with the first post in a series of tips for better folding. If you’ve already been playing for some time, you might already know most of this, but I’ll try to make sure there’s something for everyone to learn. Let’s get started!

(A note for readers of the future: if you’re reading this after this series was initially posted, I highly recommend giving yourself a few days to a week -- depending on how much you’re playing -- between each post. There’s a lot to digest here, and you’ll gain more from this series if you get some practice in-between posts instead of bingeing everything at once.)

The Basics

In every puzzle, your goal is to make a well-shaped, stable protein. Biology says "form follows function," so a beautiful shape makes an effective, stable protein and vice versa. If something looks wrong -- like it’s twisted weird or just kinda spaghetti -- that’s probably not how nature would want it. A good protein is neat and compact. It’s folded up, hence the name of the game. If a protein were just a long chain, it wouldn’t do much; it works by being a particular shape. Plus, proteins don’t like empty spaces in the middle of their shape. If there’s a gap, they’ll naturally collapse into it. But they also don’t want to be too tight -- like if you compress a spring, it’ll just fly apart when you let go. And that gets to Fundamental Folding Rule 1: Not Too Close, Not Too Far. In Foldit, things too close are "clashing" and empty spaces create "voids." Try not to have too many of either.

Okay, so we want to gently fold it up into a good shape. But what makes a good shape? We’re going to need a bit of jargon to talk about that, so get ready. <<I’ll put the extra sciencey bits like this, so if you don’t care about the details, you can skip these sections.>>

Your protein is made up of a series of segments called residues. Think of it like a long chain of bendy Lego pieces with arms sticking out of each piece. <<Each residue is an amino acid: there are 20 kinds of them in Foldit.>>

The parts of the residues that chain together are called the backbone, while the bits that stick out are the sidechains. Each residue is blue <<(hydrophilic)>> or orange <<(hydrophobic)>>.

Phew! Jargon over. Now we can talk about Fundamental Folding Rule 2: Orange In, Blue Out. Why? For now, you can think of it as oranges are sticky and blues are slippery.<<Of course, at the scientific level it starts to get more complicated as you factor in hydrogen bonds, entropy, and hydrophobic collapse. But we’ll save that for later.>>
Your protein will be submerged in water, so it needs a slippery outer coating to move around. The sticky inside helps it keep its shape by holding together like glue. If it had an orange outside, it might stick to something else and pull apart. Imagine making a paper plane with a wad of gum on the right wing. Maybe it would get stuck to the floor and you would try to pull it up, but because the gum is stuck, the whole thing unfolds. If the gum were on the inside instead, the folds would hold well together and it would be less likely to come apart. Remember: the goal is stability.

Okay, simple enough. But what if you’re stuck with a sequence like this? How are you supposed to move all the oranges to the center?

Let’s look closer at the pattern here: 2 orange, 2 blue, 2 orange, 2 blue... Nature is telling us something here -- it’s asking for a very particular and common shape, called a helix. <<Scientists use the Greek letter alpha as well, calling them α-helices.>> By making a corkscrew, we can get all the orange on one side and all the blue on the other!

Tip for the pros: Helices can range from 4 to over 40 residues!

Okay, new problem. This sequence is orange, blue, orange, blue. Our corkscrew approach won’t work because helices take about 4 residues per "turn," which is why they work well for the 2-2 pattern.

In this case, nature tends to like a different pattern, called a sheet. <<Technically, a sheet generally refers to a group of strands, where the picture below would be a single strand. A helix can be a helix by itself, but strands need to be near each other to be truly considered a "sheet." Scientists also preface sheets and strands with the Greek letter beta, as in, "β-strands." We’ll come back to this in Part 10.>>

Sheets are flat, and in Foldit they look zig-zaggy. In a sheet, sidechains alternate which direction they’re facing, so blue-orange-blue-orange, becomes all blue on one side and all orange on the other.

Helices and sheets are very stable structures -- they make pretty proteins that hold well together. Residues that aren’t helices or sheets are called loops. While loops aren’t very stable, they’re more flexible than helices or sheets, so they’re useful for making turns and connecting structures. These three types of backbone are called the secondary structures (or SS) of the protein. <<The primary structure is the sequence of amino acids.>>

But wait, what are those blue and white stripes in the picture? Those are hydrogen bonds, they form across sheets and within helices, which is part of what makes them so stable. <<Really, a hydrogen bond forms whenever an acceptor atom is adjacent to a donor and they share a hydrogen atom.And that brings me to Fundamental Folding Rule 3: Make Bonds. Hydrogen bonds are the most common, so we’ll focus on those for now. They form when one of the small blue dots is close (but not too close) to a red dot. How do you make them in bulk? Just like in the picture: build helices and line up sheets!

Tips for the pros:

  • Look for all the other ways you can form hydrogen bonds. Sidechains have blue and red dots on them too! Some even have hybrid purple dots (Tyrosine, Serine, and Threonine), which function as blue AND red.)
  • If you turn on "Show Bondable H" in the View Options, you’ll see the white hydrogen dots. Hydrogen bonds (Hbonds) need the white dot to point toward the acceptor and away from the donor.

And that’s it! Three simple rules for folding proteins. Of course, it gets more complicated, and it’s not always easy to just "add more hydrogen bonds." So in the next part, we’ll take a look at some real folds to see what these rules look like in practice. In the meantime, make sure you’re on the Foldit Discord. It’s a great place to ask questions, get help, and have fun talking to other Foldit players.

Until next time, happy folding!

Summary:

  • A protein is made of a chain of residues, each with a sidechain, connected along a backbone
  • There are three types of secondary structures (SS): helices, sheets, and loops
  • Avoid clashes (stuff too close) and voids (empty spaces)
  • Orange on the inside, blue on the outside
  • Make hydrogen bonds by lining up sheets and having helices

Ready to take on the tutorial levels? Here’s a quick guide by S0ckrates or you can look up walkthroughs on the wiki. Don’t forget to check the FAQs for some basics about Foldit.

Looking for help with coronavirus? LociOiling made a three part video series (1, 2, 3) on the coronavirus puzzles! Susume made a longer video that goes into more depth on the coronavirus puzzles.

<<Want to know more science about an intro to proteins? Check out this video!>>

agcohn821's picture
User offline. Last seen 14 hours 18 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Part 2


How to Foldit, Part 2: An Eye for Beauty

Hey folders!

Dev Josh here with the second post in a series of tips for better folding. <<Like last time, more detailed scientific information will be bracketed off like this.>>

Last time we went over the basics: the big picture of what we’re trying to do. Today we’re going to look at some examples to see what this actually looks like. Want to see this in practice? Click here for a video of a veteran folder drafting a design in a symmetric design puzzle.

Examples of Good Folds

This 2-helix, 4-sheet design comes from Bruno Kestemont from the recent coronavirus puzzles, where the goal is to make a binder protein that binds to the coronavirus spike protein (in gray). Notice how Bruno’s sheets line up very cleanly with each other and with the coronavirus. The loops are short and mostly there to connect the helices and sheets. This design is something Foldit players would also call “surfing hotdogs” because of how the helices “surf” over the sheets -- this is a very common type of design. Let’s look at a few more examples of winning solutions.

What can we learn from these examples? For one thing, helices are very strong! Silent gene’s and ZeroLeak7’s helical bundles show that. But a good line of sheets can be equally stable. We also see that “Orange In, Blue Out" isn’t a hard-and-fast rule, there can be a couple of exceptions, as shown by Skippysk8s in the upper left. <<And, in reality, hydrophobicity exists on a gradient spectrum.>>

Another type of design is the beta barrel <<so named because sheets are more formally beta-sheets, and helices are alpha-helices.>> This one comes from Murlow in puzzle 733. Each sheet is slightly curved, allowing it to make a barrel shape.

So now we’ve seen some good examples. Now let’s look at the ugly stuff: the misfolded proteins. Some of these examples come from the coronavirus puzzles again, so ignore the gray parts: we’re just looking at the protein design right now.

Examples of Bad Folds

Notice any issues? For one thing, this design doesn’t have a “core.” There’s no “inside,” so it’s free to flop about, which can cause it to pull itself apart. And although there are some helices, most of the helices are too short to be stable. The shortest helices are a full turn (4 residues), so anything less than 4 residues of a helix will just become a poor loop. Generally, you want a high volume to surface area ratio by making the protein compact rather than spread out. Okay, let’s try another one.

The helices are better here: clearly stable, nice and straight. The one in the upper left might be too short though, and it’s likely to become a really long loop. Loops are useful for their flexibility, but that comes at a trade-off to stability. A long loop like that might just flop about and start twisting on the rest of the protein, or get caught on something because it’s not tucked into the protein’s core. This protein is also taking up too much space -- notice how the helix on the bottom is not attached to anything, free to wave around from the long loop it’s connected to. There’s so much space between this helix and the others, so this is very unlikely to be how a protein would want to fold up.

Okay, this one has some sheets: what do you think of how the sheets are folded? See how the two in the center are fairly straight, but the one in the upper right curls up a bit? That’s a little weird, generally sheets will have similar curvature -- they may not always be perfectly straight, but if they’re going to curl, they’ll usually all curl in a similar way. Analogous to drawing visual art, it’s good to have a clear “line of action” in a character’s pose. Coincidentally, a protein’s fold is also called a pose.
There’s an orange sidechain exposed on the end too, which is what that yellow orb is pointing out. What about the two sheets on the bottom -- how exactly do they fit in with the overall structure? They’re lined up okay with each other, but they’re at a somewhat weird angle compared to the rest of the protein.

This one is super interesting because I originally included it as an example of a bad fold. The sheet closest to the camera is just totally misaligned, right? But I checked with our scientists, and actually this design looks really good! They said that Foldit players often try too hard to straighten their sheets, when in reality sheets are messy and bent, sometimes too long or too short, and bent a bit. Obviously, this complicates the nice simple rules we were trying to establish for what makes a good protein, but nature is messy sometimes and that’s okay. What does this mean for you? Don’t be too worried about whether sheets look perfectly straight, allow them to bend the way they want to bend!

Alright, last example for now. I’ll leave this one for you. What problems can you identify? How are the sheets, helices, and loops? Is there a core? Is there too much empty void? Have a question? Come talk about it on Discord.

Check out this page for more on aesthetics. To see more examples, check out my personal gallery of images, which includes good examples, bad examples, and real scientific models of actual proteins.

Tips for the pros: Get some practice looking at real protein models to keep training your eye.

Now that you can see what’s good and bad, how do you actually fold a protein? In the next part, we’ll look at your tools of the trade to see what you can use to make beautiful folds.

Want to keep practicing? The best way to see more examples is to join a group! In a group, you can play as an evolver, taking other players’ solutions and evolving them to be better. This is one of the best ways to get practice and see more folds. You can see the list of groups by most members or by highest leaderboard scores.

Until next time, happy folding!

Summary:

  • Helices are strongly stable but need to be at least 4 residues long
  • Helices are especially strong in a “bundle” of 3-4 helices.
  • Sheets are stable but need to be connected with a clear “line of action”
  • Loops are flexible but unstable, short loops are typically better
  • A good protein has a core with little void space in the middle
  • Common designs include “surfing hotdogs” and “beta barrels”
agcohn821's picture
User offline. Last seen 14 hours 18 min ago. Offline
Joined: 11/05/2019
Groups: Foldit Staff
Part 3


How to Foldit, Part 3: Tools of the Trade

Hey folders!
Dev Josh here with the third post in a series of tips for better folding. Please see Part 1 and Part 2 above. <<As always, more detailed scientific information will be bracketed off like this.>>

It’s time to actually get to work! Let’s look at our toolkit to see what we can use to fold our proteins. I’ll be talking about when to use each tool, so you need to know the three phases of gameplay in a Foldit puzzle:

  • Early game - This is the drafting phase. Don’t even look at your score, just go by rough shape. Mock something good up and don’t worry about minor problems.
  • Mid game - You’ve got a rough draft, now clean it up a bit. Here you’re looking for voids, clashes, and exposed oranges. You’re looking for more bonds you can make and problematic angles to straighten out. Your score will go positive during this phase and you’ll start looking at it for indications that you’re doing something right.
  • Late game - This is pure refinement. There’s actually very little scientific value in this phase, so if you’re just here for the science, you can submit what you’ve got at the end of mid game and try a different design. But if you want to get to the top of the leaderboards, you can put a few days of work into polishing out that last fraction of a point.

I’ll also mention a tool’s default hotkey, or keyboard shortcut. For tools that “run,” you can cancel them by pressing the hotkey again, or pressing Esc or spacebar to stop/cancel any tool.

Main Tools

These are your bread and butter, your go-to staples for daily folding. They’re mostly used in the early game when you’re “hand-folding,” or moving the protein manually (as opposed to running automated scripts).

Pull
The Pull tool, also sometimes called "Nudge", is the first tool you get. Click and drag to tug the protein how you want it. Pull is a useful tool for drafting your shape in the early game, especially in combination with rubber bands and freezing.

Tips for the pros:

  • Nudge is really just a local wiggle with a rubber band to your cursor. You can get more precise nudges through a combination of rubber bands, freezing, and wiggling.
  • You can turn Clashing Importance down to 0 to Pull the protein through itself without it bouncing off. This is really handy for drafting a shape in the early game without making cuts.
  • On the subject of terminology, veteran LociOiling thinks of nudges as a “short pull plus shake and wiggle” which can be useful in the early game

Shake
Shake is exactly what it says: it’s what you get if you hold the backbone steady and give the sidechains a good jostling. What’s it good for? Shake makes sure all of your sidechains are where they want to be. Typically, this means they’ll move into the space that’s least crowded, so shake is good for clearing clashes between sidechains. Shake also comes in a local variant if you just want to shake part of your protein. The default hotkey for Shake is S. <<The scientific term for shaking is “repacking”.>>

Tip for the pros: Shake is modified by the Clashing Importance.

Wiggle
Oh, wiggle. Wiggle wiggle wiggle. Wiggle is by far the most used tool in Foldit. It has single-handedly won tutorial levels as is a key player in most of Foldit’s best algorithms. At its most basic level, the gameplay loop of Foldit is (1) try something, fully knowing it will lose you many points, (2) shake and wiggle to get the points back and see if your change made it better. So what makes wiggle so good?

At a high-level, wiggle jostles the entire protein into a more comfortable shape. But really what it’s doing is making a ton of micro-adjustments to the protein: if the score goes up, it keeps that change, otherwise, it tries something else. It does this until it gets stuck and can’t find a better score. This doesn’t mean that’s the best score your pose could ever have, it just means the computer needs your help to find something better. Like shake, you can wiggle part of your protein (locally) or all of it (globally). The default hotkey for Wiggle is W.

<<Wiggle is scientifically known as an energy minimizer. It works by finding the local minimum energy (or maximum game score) in the multidimensional energy landscape. More on that here>>


Wiggle Power
In the Behavior tab, you’ll also find “Wiggle Power", which can be set to Low, Medium, (sometimes High,) or let the computer Auto-choose which power to use. Low power won’t try to compute “ideality,” or enforce proper bond angles. This is useful during the early game when you want to gently fold the protein into a rough shape. Low power keeps your fold pliable and malleable so that you can keep working with it. Medium and High power increasingly force ideality, becoming ruthless optimizers that will find every fraction of a point at the cost of hardening your protein’s shape. This kind of wiggle is good for late game refinement when you’re done making changes. If you do a high-powered wiggle too early, your pose will become hard to work with, like firing your clay before you’re done shaping it. High power wiggle is usually only available during Revisiting puzzles. For more information, check out the original blog post on wiggle power.


Fuzing
Like Shake, Wiggle considers Clashing Importance (CI). As taught in the tutorial level Control Over Clashing, this means that trying to wiggle with clashes present will result in everything flying apart. If you want to wiggle with clashes, it’s often a good idea to try shaking first to see if that gets rid of them. If you still need to wiggle with clashes, the answer is Fuzing. Fuzing (sometimes “fusing”), is a general strategy of lowering the clashing importance and then slowly raising it while wiggling. Shakes are often thrown into this process as well, for example: Shake (0% CI), Wiggle (0% CI), Shake (5% CI), Wiggle (5% CI), . . . and so on. In many fuzing strategies, the CI is lowered again and brought back up repeatedly. In fact, the fuzing recipe Blue Fuse was compared favorably with the scientific algorithm Fast Relax in a scientific publication in 2011 by the Foldit devs.

Mutate
Although this tool is only available in design puzzles, it can come in handy often. Mutate will look at all of the “mutable” (able to be mutated) sidechains and change the sidechain to a different one if the change would improve your score. Although this can be handy for quickly generating decent sidechains, the Mutate tool doesn’t think about "Orange In, Blue Out", so you might want to consider some mutation recipes. By default, press M to Mutate.

Rubber Bands
Like their namesake implies, a rubber band is a suggestion to tie two parts of the protein together. You can modify the strength (how strongly it pulls) and the length (how far apart it’s trying to pull to) of each band. Rubber bands are useful for lining up sheets (set the length to around 2 for forming hydrogen bonds; the default length of 3.5 is better for backbone-to-backbone bands), or keeping your helices straight, or generally compacting your protein by banding everything to everything else and crunching it together. You can also make a band to empty space (a Band in Space, or BiS) to tether the protein to the invisible 3D map. Another common strategy is making a bunch of bands of length 0 (Zero Length Bands, or ZLB). This has the effect of tethering your protein to where it is, so that any serious jostling will be more likely to keep its rough shape. Foldit players have found thousands of uses for bands, they are one of the most versatile tools in your toolkit. By default, press D to toggle the bands being Disabled or not, or press R to Remove all bands.

<<Rubber band lengths are measured in ångströms (symbol: Å), which is the canonical scientific unit of length measurement at the level of proteins. An angstrom is a metric unit equal to one hundred-millionth of a centimeter, or 0.1 nanometers.>>

Tip for the pros: Rubber bands can push too! If the current length is less than the band’s desired length, the band will try to push the two ends apart.

Freeze
Computers can do a good job optimizing a fold, but because they can’t see the overall shape, they don’t know what shapes are good and what shapes need fixing. Freeze is your ability to tell the computer “this is a good shape, don’t change it.” A frozen residue will not bend or move its sidechain (if the sidechain is frozen), though it can still move in space. Some uses of freeze are to limit what you’re Pulling on or to keep a structure’s shape while you’re working on arranging the pieces in the early to mid game. By default, press F to freeze/unfreeze everything, or shift-click to freeze a residue (shift + double click to freeze an entire structure).

Cut and Move
I mention these tools together because "cut and move" is a classic strategy for repositioning your protein. Clicking on your pose will bring up the Move tool, allowing you to rotate or translate the pose in 3D space. By itself, this is mostly equivalent to moving the camera unless there’s something else in the puzzle like a ligand or binding target. But by Cutting the protein into different pieces, you can Move them individually. The benefit of this, of course, is that it’s much MUCH easier to move your pose around, like Lego pieces rather than a massive structure. The drawback is that merging cutpoints back together can sometimes introduce distorted bond lengths and angles that you’ll need to clean up later. By default, wiggle will pull cuts together as if they were banded, which is good for merging the cutpoints. But you can disable this in the Behavior tab by unchecking “Enable Cut Bands.” This makes your protein pieces entirely independent.

Tip for the pros: Having trouble merging your loops back together? Try making the cutpoints in the middle of helices and sheets instead of at the loops.

Ideal SS
Similar to Idealize described in the next part, Ideal SS adjusts the angles of sheets and helices to straighten them out. This is useful in the early game, as straight sheets are easier to line up. Ideal SS is also helpful when first making structures in Structure Mode. During late game refinement, sheets and helices might want to bend just slightly, but they shouldn’t look too different from what an ideal structure would be.

Tip for the pros: You can also straighten sheets using the Tweak tool. Start tweaking a sheet, then grab the purple dot and pull it away from the sheet to straighten it out.

Modifiers
I see these tools as “support” rather than primary functions on their own, but they’re still a major part of your folding toolkit.

Clashing Importance
As mentioned above, Clashing Importance (CI) changes the percent to which tools like shake, wiggle, and mutate care about clashing. Literally, when considering if the score got better or worse, this percent is used as a multiplying factor for your clashing score. Lowering the CI is useful for Fuzing strategies, and setting it to 0 is useful when you’re just drafting in the early game. Generally, a lower CI will help the pose become more compact (since it cares less about getting too close), while a higher CI will give it breathing room.

<<Clashing is the Van der Waals force, calculated by the Lennard-Jones repulsion potential, which approximates Van der Waals forces as a function of distance.>>

Backbone pin
Hidden in the View Options, the backbone pin sets the “root” of how your protein folds onto itself. Imagine holding a piece of cooked spaghetti with two fingers: the pin is where you are pinching it. This means that the protein will be rooted to the pin, not moving much nearby, and have a great deal of flexibility furthest from the pin. There’s one pin per “piece” of your pose, so if you make a cut, you now have two pins. A backbone pin can be moved, locked, and unlocked -- while it’s unlocked, it’s allowed to slide along the protein when doing something like wiggling. But if you lock it, the pin will stay exactly on that residue until unlocked or moved. Here’s a video demonstration if you’re a visual learner. Why move and lock it? Essentially, you want to put pins on the good parts, where you want the protein to stay still. It can take some getting used to, but once you attune yourself to the physics of pinning and wiggling, the backbone pin is a powerful tool for controlling how you shape your pose.

Blueprint
The Blueprint panel is not available for every puzzle, but it can be useful in the early game when you’re drafting out a secondary structure. Blueprint offers a selection of building blocks for constructing an ideal secondary structure, in particular with ideal loops. I see it as a modifying tool because it adds “torsion constraints” to your SS. If Blueprint is available, I recommend using it in the early game for drafting a structure and then removing the constraints (by dragging the yellow rectangles outside of the panel) during the “eke and tweak” late game.

Quicksave
Although it’s not really a tool on its own, the Quicksave feature is a beloved part of every veteran folder’s toolkit. By default, ctrl+shift+[number] will save to a quicksave slot, and ctrl+[number] will load that quicksave. This can be very helpful for trying different approaches in quick succession.

Tip for the pros: can manually access quicksave slots 1-8 using hotkeys, but recipes can use quicksaves from 1-99!

Selection Interface
While on the subject of “not a tool but incredibly useful,” the Selection Interface is your key to expert folding. There are some things that can only be accomplished in this mode. The Selection Interface completely revamps your UI, changing many hotkeys and mouse functionality. In this mode, you can select a set of residues to apply a tool to, allowing you to, for example, shake exactly 12 residues and nothing else. For precision folding, this mode is a must.

That’s a lot of information, so I’ll wrap up this part for now. Next time, we’ll look at some of your tools for optimizing your pose.

Until next time, happy folding!

Summary:

  • Use Freeze and Pull or Cut and Move to draft a rough shape in the early game
  • Use Ideal SS to turn a freshly-assigned secondary structure into the perfect shape
  • Shake and wiggle (and sometimes mutate) are your primary tools for cleaning up a hand-fold
  • Rubber bands are a versatile everyday tool for adding constraints to where things should go
  • Shake and wiggle are modified by clashing importance, backbone pins, and blueprint constraints
  • The most common hotkeys are Shake (S), Wiggle (W), Disable/Enable bands (D), Remove bands (R), and Mutate (M). For more hotkeys, check the wiki.

Can’t get enough tips? Check out the Black Belt Folding series on YouTube.

Sitemap

Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, RosettaCommons