Coronavirus Designable Linker Puzzles

This week we are introducing a brand new Designable Linker Puzzle! This kind of puzzle involves two or more protein domains that are fixed in space, and players are challenged to link them with a rigid, well-folded linker that preserves the orientation of the starting domains.

Linking Coronavirus Spike Binders

Puzzle 1912b is the first puzzle of this type. This example is particularly special, as we are asking you to link two of the best known SARS-CoV-2 spike binders. These computationally-designed binders came from scientists at the Institute for Protein Design, and currently exhibit some of the best binding affinities for any known SARS-Cov-2 spike binder. The original binders are currently being developed for possible COVID-19 tests or therapeutics.

It took a large number of supercomputing hours to generate these binders, and less than 0.1% of those that were tested showed any binding affinity for the target. This goes to show just how hard binder design is! You can read more about these binders in this previous blog post. With these binders now in hand, we want to see how much we can improve them.

A model of how two designed proteins can bind the SARS-CoV-2 spike. The spike chains are shown in green, magenta and cyan. Colored in salmon are two designed binders, LCB1 and LCB3. The binders have been truncated and augmented with helices to bring their termini closer together.

The starting structure of Puzzle 1912 has a linker connecting two frozen α-helix bundles. These α-helix bundles are truncated parts of two spike binders designed by scientists at the IPD, LCB1 and LCB3. The puzzle also includes small sections of the target spike protein, although we don't need to make any more binding interactions with the spike. The goal of the puzzle is to design a rigid linker that keeps the binders in the starting orientation.

The binding affinity measures the tightness of binding between two chains, and is directly related to the change in free energy between the bound and unbound states (also known as DDG, described previously). If we can find a rigid linker that holds the two binders in a fixed orientation, we can roughly double the DDG to significantly increase the binding affinity of the linked binder.

The loopy linker in the starting structure won’t work because it will be too flexible in solution. The two binder domains will flop around and behave independently, like two separate binders. However, if the linker were well-folded and rigid, the two binder domains could behave like a single protein with double the binding surface.

The starting structure for Puzzle 1912. The helical binding domains and small portions of the spike are frozen. In green is the designable linker that needs to be folded.

How to Score Well

Designed linkers with lots of secondary structure (sheets or helices) will score better and be more likely to do the job. We're looking for linkers that hold the binders in the proper orientation with more rigidity than a flexible alanine chain. We are using a few objectives to encourage well-folded linkers, including the Core Exists and SS Design Objectives. The BUNS Objective is also active on the linker.

We look forward to seeing how Foldit players solve this problem! Promising designs may be tested at the IPD for improved binding to the spike. A tighter binder would be especially useful for detecting small amounts of coronavirus in a fast and sensitive diagnostic test.

The Future of Designable Linker Puzzles

Rigid linker design is an outstanding problem in protein design. It is made especially difficult by the fact that the connected domains are constrained to their starting position, and the designed linker cannot clash with other chains nearby (like the binding target).

Scientists have been trying to develop computational methods to design rigid linkers from scratch, but have not had much success. They suffer from limitations that don't apply to Foldit players, and we think that human ingenuity and hands-on problem solving might be the answer to this problem.

Check out the Designable Linker: Coronavirus Spike Binder puzzle now!

Happy Folding!

( Posted by  neilpg628 98  |  Tue, 11/03/2020 - 21:43  |  0 comments )
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