Foldit Puzzles

Design of the Month: February 2021

This sandbox puzzle features a symmetric tetramer assembly, designed by silent gene in Puzzle 1941. This design has a strong core and a nice H-bond network, but look out for buried unsatisfied polar atoms (BUNS) at the interface between subunits! For more, check out Foldit Lab Report #17 on YouTube! This sandbox puzzle is non-competitive and will not award any points.

1959: Two-sided Interface Design

Design an interface between two protein chains! This puzzle is much like Puzzle 1950 but we've piled on some more Objectives to reward a H-bond Network at the interface, as well as a single disulfide bond at the interface. In this two-sided design puzzle, you can mutate the interface residues of both chains A and B, but you may only shape the backbone of chain A. The goal is to create a binding interface between the two protein chains so that they will stick together in solution. However, the starting position of the two chains is important, so the locked regions are held in place by strong constraints. The only way to make the two chains bind will be to fold up a brand new interface between them.

1958: BAM Complex with Electron Density

This is a followup to Puzzle 1952, now starting from the structure that was originally published. This protein is part of a large protein complex with multiple subunits, which was recently solved by cryo-electron microscopy (cryo-EM) at 4.2A resolution. Unfortunately, the solved structure could really use some work so we are hoping you can improve the structure. The starting structure also includes several locked protein fragments in the electron density cloud. These are additional proteins that are also present, and are expected to make interactions with the final folded structure. Good luck!

1957: Designable Linker: Coronavirus Spike Binder

This is the fourteenth puzzle in the designable linker series! We are providing parts of two of the best-known designed binders to the SARS-CoV-2 spike, and are challenging players to link them together with a rigid linker! One of them is LCB3 which you have seen before, but the one without any adjoining spike is called AHB2, and is another de novo protein that is meant to mimic ACE2, which is the human protein that SARS-CoV-2 binds to when it infects your cells. The two helical bundles are the parts of the two binders. They are currently connected with a flexible alanine linker that needs to be redesigned.

1956: Influenza HA Binder Design: Round 2

Design a protein to bind to influenza virus! This puzzle has a Move Limit of 250 moves; after that, you will be unable to improve your solution, but you can restart the puzzle to reset your move count. The Move Limit is meant to encourage players to try multiple solutions to the puzzle, instead of spending a lot of time optimizing a single solution.

1955: Revisiting Puzzle 55: Scorpion Toxin

This is a throwback puzzle to the early days of Foldit. This scorpion toxin binds to voltage-gated ion channels in insects, resulting in full-body paralysis. The protein contains eight cysteine residues that oxidize to form four disulfide bonds. We are revisiting old Foldit puzzles so we can see how useful the recent additions to the game have been and to provide newer players with problems that are still scientifically relevant.

1954: Symmetric Tetramer Design: H-bond Networks

Design a symmetric protein tetramer, with 4 identical chains that assemble together! This puzzle includes a Secondary Structure Objective, so no more than 50% of your design can form helices. The H-bond Network Objective encourages players to build buried, satisfied H-bond networks at the interface between symmetric chains. H-bond networks are a great way to introduce polar residues at the interface, but it's important that all of the bondable atoms make hydrogen bonds! We've also adjusted the H-bond Network Objective so that poor-scoring H-bonds may not contribute to networks; poor-scoring H-bonds will be displayed in red. This puzzle uses the Buried Unsats Objective, with a large penalty for buried polar atoms that can't make H-bonds. In this puzzle, there are no limits on the Complex Core, but we've included the Complex Core objective so players can see the core residues that can be incorporated into H-bond Networks.

1953: Influenza HA Binder Design

Design a protein to bind to influenza virus! The hemagglutinin (HA) protein is displayed on the surface of the influenza virus, where it can bind to receptors on human cells. Once the HA protein binds to a human receptor, the entire HA protein changes shape, springing open to trigger membrane fusion so that the virus can infect the human cell. We want to design a protein that can bind to the pre-fusion shape of HA, to stop it from springing open and thereby blocking infection.

1952: BAM Complex with Electron Density

This protein is part of a large protein complex with multiple subunits, which was recently solved by cryo-electron microscopy (cryo-EM) at 4.2A resolution. Unfortunately, the solved structure could really use some work so we are hoping you can improve the structure. One end of the unfolded chain is close to its correct position in the electron density, but the rest of the chain is completely extended and will need to be refolded to fit in the density cloud. Keep in mind that this will not be easy, as 4.2A resolution results in a challenging electron density cloud to work with! The starting structure includes several locked protein fragments in the electron density cloud. These are additional proteins that are also present, and are expected to make interactions with the final folded structure. Good luck!

1951: Designable Linker: Coronavirus Spike Binder

This is the thirteenth puzzle in the designable linker series! We are providing parts of two of the best-known designed binders to the SARS-CoV-2 spike, and are challenging players to link them together with a rigid linker! One of them is LCB3 which you have seen before, but the one without any adjoining spike is called AHB2, and is another de novo protein that is meant to mimic ACE2, which is the human protein that SARS-CoV-2 binds to when it infects your cells. The two helical bundles are the parts of the two binders. They are currently connected with a flexible alanine linker that needs to be redesigned.