Aβ Binder Redesigns and the Round 2 Puzzle

In two previous blog posts (here and here), I wrote about the challenges of creating a protein to bind the Aβ polypeptide, a naturally-occurring polypeptide in the brain which self-assembles in Alzheimer's disease to produce toxic, aggregated forms that somehow kill brain cells. I've had a chance now to go through the designs that players created for the first Aβ Binder Redesign puzzle, and I've got to say that I'm very impressed. The goal was to redesign an existing, symmetric protein consisting of a pair of identical subunits in order to break the symmetry of the binding interface and optimally bind the Aβ molecule. The best designs that you produced achieved this beautifully – so congratulations!

We're still a few steps away from being able to test these designs in the wet lab, however. We first need to stabilize the structure a bit more with some more secondary structural elements, and then connect the two subunits to make one long chain. In the current puzzle, we would like to add a couple of additional β-strands to the β-sheet formed by the binder and the Aβ polypeptide. Ideally, these should pack well against the flanking helices, should hydrogen-bond perfectly to the adjacent β-strands, and should present core side-chains that pack without voids with the existing core (which you can redesign as needed). Here's a rough illustration of the backbone configuration that I'm hoping to see:

Desired backbone conformation for the current puzzle

This puzzle is a prelude to a subsequent puzzle in which we will change the loop connectivity to make the binder into one long chain (instead of two separate chains) – which means that you need not worry much about the loops in this puzzle. We have chosen as starting points nine of our favourite designs from the first puzzle. Congratulations to the following players for their excellent designs:

-------Player------- -------Team-------
MurloW, wisky Anthropic Dreams
johnmitch (none)
LociOiling (none)
silverberg (none)
andrewxc Richard Dawkins Foundation
SKSbell (none)
cobaltteal (none)
matosfran (none)
deLaCeiba (none)

The designs that we selected tended to be high-scoring designs, but this was not the only criterion that we considered. In particular, we paid close attention to good packing in the core and at the binder-Aβ interface (i.e. to the absence of deeply-buried voids). Small voids in the spaces between polar, surface-exposed residues are often less important, since water molecules can happily fill those.

This brings up a good point: the score assigned by the Foldit game engine is not a perfect representation of how “good” a structure is. This makes the game a little bit unfair for the players, but this isn't due to malice on our part: we'd like to make Foldit as fair a game as we possibly can! The truth is, improving the scoring is quite difficult, and it's an area of active research for the scientists who try to model protein folding computationally. We are constantly trying to develop better means of evaluating, mathematically, how likely it is that a particular computer model of a protein represents reality. The more reliable we make our scoring functions, the better we can predict in advance what's likely to fold up in the test tube, and the fairer Foldit becomes since the highest-scoring designs become the ones that are most likely to be good designs in reality. Because this is a very difficult problem that we have not fully solved, we still need to do a lot of manual checking to determine whether a design really is plausible or not, which means that, while players should use the score as a guide, there are structural features (like voids) that you should also pay close attention to.

(As an aside, scoring is one of two fundamental problems in the computational protein folding field. The other big area of research is devising algorithms to search for good structures given a protein sequence, or good protein sequences given a desired structure that we'd like to design. Just as computers were taught to play chess by emulating human players, we would like to solve this second problem by emulating the way in which the most skilled humans fold proteins by hand. This is the whole point of Foldit!)

( Posted by  v_mulligan 70 1803  |  Tue, 11/19/2013 - 08:35  |  5 comments )
wisky's picture
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Whose structure corresponds to which structure number, if I may ask?

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Same order as above

The order of the list above has been preserved in the order of starting structures for Puzzle 811 (so Structure 1 is the design by MurloW and wisky, Structure 2 is the solution by johnmitch, etc.)

Note: there was an error in the original post, where MurloW and wisky were listed as separate authors of two different designs, and deLaCeiba was omitted from the list.

wisky's picture
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Ahhh!!! It makes sense, thank you very much :)

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My mistake!

Sorry about that -- the error in the list was my mistake.

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