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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.

Sneak Peak - The Trim Tool

We wanted to give players a sneak peek at an exciting development project that is currently in progress.

The Foldit team is always looking for ways to allow players to tackle new types of problems. One of the biggest obstacles we run into when trying to design a new puzzle is protein size. Many potential puzzles never get past the planning phase because they simply contain too many residues.

Currently, Foldit can only handle a little over a hundred residues before the interface and tools start grinding to a halt - especially on lower spec machines. In some instances, we have run puzzles with more residues than this, but we’re still limited to a few hundred in the best of situations. We’re always torn between providing you with the latest interesting challenge while also trying to keep the client responsive.

In an upcoming release, users will be able to try out a feature that has been designed to help solve this issue: the Trim tool (name is a work in progress!).

The Trim tool, along with the corresponding Untrim tool, will allow Foldit users to focus on specific regions of a protein in isolation, as if these regions are their own, smaller puzzles.

With the use of the new selection UI, users can select any region—or set of regions in a puzzle—and then click on the Trim button in order to create a new structure containing only the residues that had been selected.

After operating on this trimmed structure with all of the features normally available for a Foldit puzzle, users will be able to introduce the changes to this region back into the full puzzle, using the Untrim button.

We hope you have enjoyed this feature preview! We are still solving technical challenges and finalizing the behavior of the Trim tool, but we hope to release it in early 2022. We are already excited about the potential of this new set of tools, and look forward to seeing what Foldit players can do with them!

( Posted by  jflat06 45 320  |  Tue, 12/21/2021 - 07:30  |  2 comments )
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IL-2R binders queued for testing

Starting in summer 2021, we ran 6 rounds of IL-2R binder design puzzles. Now we’ve selected 115 promising Foldit designs to test for binding in the lab! In early 2022, we will conduct a FACS experiment to test if these protein designs successfully bind to the IL-2R target.

Targeting IL-2R for cancer treatment

IL-2R is a protein found on the surface of human immune cells, and is composed of three different protein chains (α, β, and γ). Due to its role in regulating the immune system, IL-2R is an important target in cancer immunotherapy. However, IL-2R drugs are associated with severe side effects that seem to arise from over-activation of the α chain.

The goal of the Foldit IL-2R puzzles is to design a protein binder for the α chain of IL-2R, to block over-activation by immunotherapy drugs. The designed protein could potentially be given to cancer patients alongside normal immunotherapy to reduce its side effects. (In a different approach, other researchers have recently designed a protein binder for IL-2R β/γ that avoids the α chain altogether; that protein is currently in Phase I clinical trials.)

Selecting Foldit solutions for testing

We analyzed the solutions from all 6 IL-2R Foldit puzzles and selected 115 solutions based on their Foldit score and the binder metrics DDG, Contact Surface, and BUNS.

For this experiment, we did not factor in AlphaFold confidence when selecting designs to test, even though the AlphaFold tool was available in some of the IL-2R binder puzzles. However, most of the selected designs have AlphaFold confidence greater than 75%, so we think they have a good chance of folding.

2011731_c0001 Crossed Sticks
2011731_c0007 grogar7
2011731_c0008 Galaxie
2011731_c0013 stomjoh
2011731_c0018 ucad
2011731_c0019 fpc,frood66
2011731_c0024 Mike Cassidy
2011731_c0026 jobo0502
2011731_c0029 robgee
2011731_c0032 fiendish_ghoul
2011731_c0038 Bruno Kestemont
2011731_c0063 mirp
2011731_c0145 alcor29
2011731_c0151 LociOiling
2011852_c0001 Bletchley Park,BootsMcGraw
2011852_c0003 dcrwheeler
2011852_c0005 sallallami
2011852_c0009 alcor29
2011852_c0010 grogar7
2011852_c0012 ZeroLeak7
2011852_c0013 OWM3
2011852_c0017 NeLikomSheet
2011852_c0020 stomjoh
2011852_c0028 Mike Cassidy
2011852_c0029 Bruno Kestemont
2011852_c0032 Bruno Kestemont
2011852_c0035 dcrwheeler
2011852_c0044 silent gene
2011852_c0047 spvincent
2011852_c0048 robgee
2011852_c0082 dcrwheeler
2011852_c0128 ShadowTactics
2011852_c0164 BootsMcGraw
2011926_c0001 Crossed Sticks
2011926_c0002 Galaxie,grogar7
2011926_c0003 toshiue,Bruno Kestemont,Phyx
2011926_c0004 Bletchley Park,spvincent
2011926_c0007 Bruno Kestemont
2011926_c0009 Mike Cassidy
2011926_c0011 Bletchley Park
2011926_c0012 dcrwheeler
2011926_c0014 LociOiling
2011926_c0015 fpc,jausmh
2011926_c0016 robgee
2011926_c0018 HuubR,Keresto,ManVsYard
2011926_c0022 ShadowTactics
2011926_c0025 Phyx
2011926_c0028 spvincent
2011926_c0038 NinjaGreg,toshiue
2011926_c0041 fiendish_ghoul
2011926_c0051 dcrwheeler
2011926_c0061 Bletchley Park,spvincent
2011926_c0068 dcrwheeler
2011926_c0073 dcrwheeler
2011926_c0102 dcrwheeler
2011926_c0152 LociOiling
2011926_c0172 LociOiling
2011926_c0233 ShadowTactics

2011958_c0002 sgeldhof
2011958_c0005 Enzyme
2011958_c0011 Crossed Sticks
2011958_c0039 blazegeek
2011958_c0043 robgee
2011958_c0048 Enzyme
2011958_c0049 silent gene
2011958_c0051 Enzyme
2011958_c0055 Enzyme
2011958_c0056 Enzyme
2011958_c0062 LociOiling
2011958_c0063 Phyx
2011958_c0077 Enzyme
2011958_c0083 blazegeek
2011958_c0085 Todd6485577
2011958_c0094 mirp
2011958_c0097 alcor29
2011958_c0106 robgee
2011958_c0117 dcrwheeler
2011958_c0122 akaaka
2011958_c0165 Galaxie
2011958_c0176 fiendish_ghoul
2011958_c0249 mirp
2012023_c0003 sgeldhof
2012023_c0004 silent gene
2012023_c0005 nspc
2012023_c0007 Bruno Kestemont
2012023_c0020 Galaxie,grogar7
2012023_c0022 LociOiling
2012023_c0023 Galaxie
2012023_c0025 akaaka
2012023_c0029 alcor29
2012023_c0035 Bruno Kestemont
2012023_c0036 ichwilldiesennamen
2012023_c0038 Bruno Kestemont
2012023_c0071 BootsMcGraw
2012023_c0079 PLAYER_1
2012023_c0110 Galaxie
2012023_c0122 LociOiling
2012150_c0001 nspc
2012150_c0002 spdenne
2012150_c0027 LociOiling
2012150_c0032 Crossed Sticks
2012150_c0034 sgeldhof
2012150_c0043 Enzyme
2012150_c0046 Bruno Kestemont
2012150_c0048 nspc
2012150_c0053 gmn
2012150_c0054 robgee
2012150_c0055 alcor29
2012150_c0057 dcrwheeler
2012150_c0059 alcor29
2012150_c0070 Bruno Kestemont
2012150_c0093 Bruno Kestemont
2012150_c0113 zippyc137
2012150_c0133 Galaxie
2012150_c0147 LociOiling

The binding experiment will follow the same template that we’ve used before to test for binding against SARS-CoV-2 spike, MERS-CoV spike, and IL-6R.

We start with the amino acid sequence of each protein design and reverse-translate it into a DNA sequence. This custom DNA is ordered from a specialized company, and the DNA is inserted into yeast so that the yeast cells can produce our proteins and display them on the cell surface. Finally, we use fluorescent tags and microfluidics technology to sort out the yeast cells that can bind to our target protein--in this case, the α chain of IL-2R. See this blog post for a full description of the experiment.

Diversifying the testing pool

To increase our chances of success and make the most of Foldit players’ work, we again used a grafting technique to expand the diversity of the 115 Foldit designs.

We combine the binding interfaces from Foldit solutions with a large library of stable scaffold proteins to make variations of the original Foldit designs. This boosts the number of proteins in our testing pool, and allows us to more thoroughly test the binding interfaces designed by Foldit players. Our grafting method is described in more detail in this previous blog post about binders for MERS-CoV spike.

Diversifying the testing pool helps to bank against cases where the interface looks good but the binder protein fails to fold correctly. If your binder protein misfolds, then the interface residues will not be correctly positioned to bind the target. It doesn’t matter how good your DDG or Contact Surface metrics look if your protein design doesn’t fold!

By grafting the interface residues of each Foldit design onto a diversity of protein scaffolds, we generate multiple designs with the same interface, but with (potentially) very different folding behavior. This maximizes the chances that at least one of these proteins will fold correctly and present the designed interface to bind the target as intended.

We used this grafting method to generate over 1700 variations of the original 115 Foldit designs. Together with a third set of experimental re-designs (described in a future blog post), we’ll be testing a total of 1997 IL-2R binder designs from the work of Foldit players. These will be tested at the Institute for Protein Design alongside 30,000 additional designs from IPD researchers.

A big thank you goes to all Foldit players who participated in our IL-2R binder puzzles! We are very excited to get some experimental data about how these Foldit solutions behave in the real world. Keep an eye out for experiment results in the early months of 2022. In the meantime, happy folding!

( Posted by  bkoep 45 252  |  Thu, 12/16/2021 - 00:26  |  1 comment )
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New Foldit Interface

We are excited to release a new, single interface for Foldit.


One of the issues we’ve had in Foldit development is supporting both of the prior interfaces (Original Interface and Selection Interface). Not only does it take more effort to write to implement features in both interfaces, it’s also something of a user support issue, as it’s difficult for new players to come in learning one interface, and then get help from the documentation and experienced players for the other interface.


People with familiarity with the old Selection Interface will see similarities with the new interface, as we leaned heavily on the behavior of the Selection Interface for the new UI. (Selection interface is the preferred interface of a number of top users and the Foldit team, as well as allowing more flexibility for future improvements.) Most importantly, we kept the “selection” mechanic from the Selection Interface. To work on sub-sections of the protein, first select segments by clicking (and/or shift-clicking, ctrl-clicking [cmd-click for Mac] or double clicking) those sections you want, then select the action to use. Simply click the background to deselect segments and return to global actions.




Menu Panel: The Menu Panel can be accessed by clicking the Foldit icon in the upper left corner. This allows you to access overall game controls like changing puzzles, saving/loading solutions and exiting the program.


Puzzle Title: Click on the Puzzle title to go to the web page for the puzzle. (Try it on intro puzzles!)





Score Display: We’ve simplified the score display to focus more on the thing that counts -- your score.





Objective Panel: Previously, in puzzles with a large number of objectives, having the objective panel directly underneath the score meant that expanding it would block the main display. We’ve moved it off to the side, to lessen the interference when it’s expanded.





Side Buttons: For easy access, a number of panels can be accessed from convenient buttons on the left hand side of the screen: Help, Undo, View Options, Behavior Options and the Cookbook





Action Bar: Similar to the old Selection Interface, most of the actions you’ll use in working with the protein are found in the action bar. Unlike the SI, though, all the actions which are available on the puzzle should be present from the start - they may be disabled until you have the correct selection (check the tooltip on disabled actions), but they’ll be present. If you’re familiar with the Original Interface, the actions from the action popup menu and the right-click pie menu will now be found at the bottom of the screen.


No Modes: Gone are the “Modes” from the Original Interface. Instead, all functionality from the independent modes are available in the action bar. No more switching back-and-forth!


Mouse Control: The control of the view by clicking on the background should be unchanged. Use (left) click (either single or double, potentially while holding shift or ctrl [cmd for Macs]) to select residues. (Left) Click and drag does pull. Right click [control-click for single button Macs] can freeze a segment, double right click will freeze a region, and right click and drag will add a band.





View options: The behavior of the View Options menu has gotten an update. We’ve added support for view presets. This should allow you to develop your own customized combinations of view settings for different purposes, and easily switch between them. It will also allow us to put out suggested per-puzzle view settings, such that design puzzles can get a different default view from electron density puzzles or ligand puzzles.





To use a preset, simply select it from the list. You can also create a new preset from the current settings, edit the current preset, or delete your custom preset. Editing a preset brings up the customization options. These will only change your preset if you actually Save the preset, or return to the preset list (keeping the current view settings, but without changing the preset.)

The Future

We’re excited about the new, unified interface. This should allow us to more rapidly implement improvements to the program and the UI. We’re open to suggestions on how to make the new user interface more useful for all Foldit users.


Wondering where things went? We’ve put together a short guide on where various buttons and functionality have moved to.

( Posted by  rmoretti 45 272  |  Tue, 11/16/2021 - 18:17  |  32 comments )
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PROTAC small molecule design project

We’re happy to officially announce an ambitious new scientific project making use of the updated Small Molecule Design tool

Controlled protein degradation

Your cells need to constantly recycle old proteins. One way they do this is by tagging unneeded proteins with a specific signal molecule (ubiquitin) which sends them to the proteasome where they are cut up into individual amino acids. The ubiquitin tag itself is sufficient to cause the protein to be degraded, so the cell has a number of complex signalling pathways which normally control which proteins get tagged at what time. (This is the E1/E2/E3 enzyme cascade.)

Proteolysis targeting chimeras (PROTACs) are an exciting new approach to hook into that system, to promote degradation of proteins which wouldn’t otherwise be degraded. They work by having one end which binds to the protein to be destroyed, and another end which binds to an E3 ubiquitin ligase. Simply by binding to both proteins and bringing them together, a PROTAC causes the E3 ubiquitin ligase to tag the nearby target protein with ubiquitin and thus send it for degradation. The beauty of the system is that the portion of the molecule that binds the target and the portion which binds the E3 ligase are completely independent, connected by a generic linker. This makes it much easier to develop the parts separately and then combine them.

Not only are PROTACs an exciting possibility for developing new drugs, they’re an excellent research tool to figure out how proteins work in cells and organisms. Current approaches for gene function research rely heavily on “knockout” studies in model organisms, where the gene is removed entirely. This approach has limitations in that you can’t control when and where the protein is removed (it’s removed from everywhere always). It also requires difficult and costly genetic manipulation of the organism. PROTACs allow you to control the timing of protein removal by when you apply the drug, and by which E3 ligase you target. And you can do this in unmodified “wildtype” cells and organisms.

Specificity needed

Currently, we’re somewhat limited by the number of small molecules which can target E3 ubiquitin ligase. Humans have over 500 different E3 ligase genes, each with their own expression profile and localization. We have comparatively fewer small molecules which can bind to the E3 ligases, and the ones we do have aren’t necessarily great for drug purposes. (Thalidomide is a popular choice for research purposes.) This limits the control we have over when and where the PROTACs work.

We hope you can change that! Using the small molecule design tool, you can make small molecules which bind to an E3 ligase, and thus can be a potential base for future PROTACs. The hope is that by developing a library of compounds which bind to different E3 ligases with different specificities, we’ll develop an arsenal of PROTAC-halves which can be used by future researchers. They’ll only have to worry about finding a binder to their protein of interest, and can then take an E3 ligase binder “off the shelf” and “simply” connect the two. With a library of E3 ligase binders, they can use the same protein of interest binder and target different E3 ligase binders, depending on their purposes.

The initial E3 ubiquitin ligase we targeted was the von Hippel-Lindau tumor suppressor protein (VHL). VHL has already been shown to be useful as the E3 target of PROTACs, and there’s existing publications showing what makes a good VHL binder. However, the existing binders are not particularly “drug like”, so we thought there was plenty of room for Foldit players to improve the state-of-the-art. To get an update on the status of VHL designs, check out the most recent VHL Ligand Design Blog Post

Compounds will be tested - will yours?

We’ve teamed up with a major pharmaceutical company - Boehringer Ingelheim (BI) - for this project. They approached us, wondering how they could support the small molecule design efforts in Foldit. BI has a history of supporting open science, for example creating opnMe to share BI-generated molecules. They are excited about the possibilities citizen science has in supporting open research in small molecule drug design, and think Foldit is a great way to achieve this.

Boehringer Ingelheim has committed to help evaluate and test the molecules which Foldit players have designed. Molecules you create in Foldit will be passed on to the team at BI, who will evaluate them based on the same criteria used for their own internal small molecule development. Compounds which pass the test will then be synthesized and tested for binding by BI. They have also volunteered to try to determine the crystal structure of successful protein-small molecule complexes, so we can better determine how well the Foldit design matches the actual experimental structure.

All participants and game sponsors of current and future small molecule design games commit to complying with the Foldit Terms of Service including those pertaining to intellectual property.

All compounds created as part of the collaboration puzzles will be made publicly available. Experimental results from testing the molecules will also be released publicly.

( Posted by  rmoretti 45 272  |  Wed, 10/20/2021 - 21:11  |  0 comments )
0

Small Molecule Design Tool

The highly anticipated updates to the Small Molecule Design Tool are here, and we have a series of puzzles on the way! Your continued efforts in protein design have been nothing short of remarkable, and we are excited to be able to further help this amazing community contribute to small molecule design. While protein based drugs are an increasingly important category of therapeutics, the majority of drugs continue to be small-molecule based. With the Small Molecule Design tool you will be able to create, edit, and enhance small molecules.

Let's dive in and see how the Small Molecule Design Tool works. The tool will come up as an option in the Selection Mode action bar when you select a designable small molecule on a puzzle which supports it. With the Small Molecule Design Tool open, you can select particular atoms in the designable ligand to act on. The tool has two distinct panels: Atom Selection and Fragment Selection. You can toggle between them with the central Panel Selection Button.

The Atom Selection Panel has two unique areas: The Atom Selection area at the top and the Bond Selection area in the middle. With Atom Selection, selected atoms can be replaced with an atom of your choosing, assuming the placement is allowed. With Bond Selection, you will be able to select two atoms, and change the bond type between them.

The Fragment Selection Panel works with groups of atoms. The category buttons in the middle organize the fragments into four separate groups: Functional Groups, Unsaturated Cyclic, Saturated Cyclic, and Polycyclic. Each choice will change the contents of the Fragment Selection area above. Once you’ve selected the type of fragment, you can select the location (the atoms) on the small molecule where you want it to go, and then select which fragment you want from the Fragment Selection area. This will pop up a sub-panel which allows you to select where on the fragment you want to place the attachment. Using the `A`, `S` and `TAB` keys while hovering over the selection in the subpanel will allow you to further customize how the fragment is placed.

You may have noticed that both panels share a couple of elements. These are the Panel Selection Button, which allows you to switch between the Atom Selection Panel and the Fragment Selection Panel, and the Cleanup Structure area, with which you can delete atoms, delete bonds, and deselect highlighted atoms.

Be sure to check out the new tutorials to help get you started! We can't wait to see what all you come up with. Happy building!

( Posted by  Sciren 45 199  |  Tue, 10/12/2021 - 21:45  |  4 comments )
1
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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, Boehringer Ingelheim, RosettaCommons