Alzheimer's puzzle update from Baker Lab scientist Vikram Mulligan

In an earlier blog post, I wrote about the challenges of designing a protein therapeutic for Alzheimer's disease. Such a molecule must be able to bind with both high affinity and specificity to the neurotoxic Aβ polypeptide that causes the disease. Furthermore, the binding must prevent Aβ from self-associating to form neurotoxic protein oligomers or aggregates. In addition, a successful protein therapeutic must be stable in the body for a long time, evading clearance by the immune system and by proteases. It must also be able to cross the blood-brain barrier. Ideally, we would also like to add some functionality that would allow one binder molecule to clear or break down many Aβ molecules, though this will be an additional challenge. All of these are difficult problems to solve, but by breaking the overall goal into its component parts, we can begin to address these one at a time – and Foldit players can help!

The first puzzle that we posted involved the redesign of the core and interface residues of an existing, homodimeric Aβ binder in order to break the symmetry of the binding interface and improve both the affinity and the specificity for the asymmetric Aβ molecule. I am currently examining the designs that players produced in Puzzle 801b (many of which look quite impressive), and we will be revisiting these designs in the near future with a new puzzle. This puzzle will involve linking the secondary structural elements with new loop regions (which Foldit players will design) in order to convert the homodimer into a single large, monomeric protein. As we prepare the follow-up puzzle, we also want to get players started on a parallel strategy that we'll be exploring: complete de novo design of an Aβ binder.

In the new de novo design puzzle, we will be giving you the Aβ polypeptide in a rigid backbone conformation that has been observed in the complex with the affibody binder in NMR studies. We will also be giving you eight short, separate peptides (two of 24 residues, two of 20 residues, and four of 10 residues). We would like you to pretend that these short peptides are secondary structural elements of a single-chain protein, in which these peptides would be linked by loops – but we'll worry about the lengths, conformations, and sequences of the loops in a subsequent puzzle. For now, we'd like you to assemble these components around the Aβ polypeptide in such a way as to favor high-affinity, high-specificity binding. We are starting half of these peptides out as helices, and the other half in extended, strand-like conformations, but you should feel free to change the secondary structure as you see fit in order to achieve excellent binding. While the Foldit score should guide you, keep in mind that there are features that we are looking for that are not always captured well by the score alone. A successful design will have excellent shape-complementarity between all of the components – i.e. the surface of each element should have bumps and grooves that pack tightly against the surface of the next element. In addition, good designs should have buried hydrophobic residues making the core (phenylalanine, methionine, isoleucine, leucine, tyrosine, valine, and tryptophan). The surface should be non-hydrophobic. Most of the Aβ polypeptide's hydrophobic surface should be buried by the binder, both for purposes of specific recognition and to prevent Aβ from engaging in hydrophobic interactions with other, unbound Aβ molecules. Voids in the core of the binder or in the Aβ-binder interface are a bad thing – they're rarely seen in natural protein structures, and are energetically very unfavorable, though it is difficult for us to capture this properly in the mathematics of the Foldit score.

I'm also interested in your feedback about how this type of puzzle feels – in part because, if this turns out to be an effective means of designing a protein to bind a target, I'd like to try to develop automated algorithms to do the same, emulating the strategies used by the best Foldit players. Do you like having the freedom to move secondary structural elements independently, or is this too open-ended and unconstrained a puzzle? Does this open up new strategies that you would not have if you were dealing with a single long chain? Can you think of new Foldit manipulation tools that would make this type of puzzle easier for you? Would you like to see more design puzzles of this type, with follow-up loop design puzzles, or do you prefer the classic, “fold-a-long-chain” type of puzzles?

Please leave your comments below!

( Posted by  bkoep 89 825  |  Tue, 11/12/2013 - 00:09  |  10 comments )
spdenne's picture
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Show Isosurface is incomplete

Three helices and one sheet are not shown with isosurface when you turn on the show isosurface view option.

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At least we have an overview on all elements and a proposed SS

Not like in a long chain (what I personally don't like to start with).

Exciting because we have the impression to help in a quite transparent scientific process. Even if I'm not sure to understand all the Science of it. May be some player like susume will translate the Science to our player's language ...

Joined: 12/06/2008
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not enough direction given

I've seen several designs where the AB polypeptide --- the two rigid sheets --- is completely surrounded by the eight sections of mutable polypeptide.

This configuration can't exist, if I understand what it is we're trying to do. It's probably at this time impossible to code the scoring for it, but there should at least have been more explanation offered, stating what is and is not physically possible. The complete free reign allowed in the puzzle will foster tons of high-scoring, but useless solutions.

wisky's picture
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Sounds like every other

Sounds like every other design puzzle we've had (tons of high-scoring, but useless solutions), except that this will provide a chance to look at many different interfaces with the Abeta proteins.

wisky's picture
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I like it

I like it, but there is too much free reign on this specific puzzle. Designing 128 individual residues around a small chain is a very daunting task. I would love to see more of these puzzles, and more of the traditional "denovo" straight chain design puzzles.

v_mulligan's picture
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On BootsMcGraw's point

Your comment raises a good point, BootsMcGraw. The truth is, we didn't want to give too much direction because we don't know in advance exactly what will work and what won't, and we don't want to limit ourselves to what we might think of in the lab. What would help us the most would be to see many, many diverse designs from the Foldit players, even if only a smallish subset turn out to work.

The specific example of the ABeta molecule surrounded on all sides by designed chains is not necessarily something that we want to discourage. There are protein binders that deeply bury the thing that they bind, so that is a possible binding mode. It's counter-intuitive, of course -- the immediate question is, "How on earth does the bound molecule get in and out of the binding site?" -- but such a design could be useful.

(Interestingly, a buried binding site will affect the speed with which a molecule is bound and released, but tends not to determine the final probability of having a molecule in the binding site once the system has had time to achieve its equilibrium between bound and unbound states. On the molecular scale, "slow binding" could mean seconds rather than milliseconds or microseconds, so it's still fast enough for our purposes.)

gitwut's picture
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Positioning is tedious

As with using cutpoints, positioning the fragments is tedious. Whereas with cutpoints you can join them and move a group intact that can later be cut apart again, you can't with these fragments. Each piece has to be moved and positioned separately.

In this respect, I see the current puzzle type as working with non-closeable cut-point mode where "enable cut bands" is turned off. We are disadvantaged since it makes it harder to determine node numbering (to see which fragment ends will eventually connect).

I vaguely remember someone suggesting once that selecting multiple cut segments be implemented in the select interface, though I'd recommend making it possible with the move tool (or whatever non-select mode is called) too.

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Multiple cut fragments

I'm a total novice, with no chemistry since 1974 and that was high school. So ignore if this is not helpful. I like the independent pieces of the puzzle, but would love to be able to group up some chunks and move them around. I tried various configurations to see what would work well from a points standpoint. I would hope that might also prove useful from a results standpoint. A little "english" direction about what the end design needs to do might help me focus on solutions that would be more useful from a lab standpoint.

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The group-moving idea

A couple of people have suggested that it would be useful to be able to move groups of fragments together. I'll definitely pass that idea along to the Foldit programmers -- it makes sense.

@Skippysk8s: I know that the direction for this puzzle was a bit vague, but we didn't want to give you too much direction because we don't want to constrain you to our preconceived notions of what a binding protein "should" look like. What I'm hoping for are very diverse designs for proteins that bind tightly to Abeta, fully burying Abeta's hydrophobic parts. I know that's vague, but I hope that players will feel very free to explore many different ways of packing bits of protein around Abeta. I'll be looking for good hydrophobic burial, good hydrogen bonding (especially of buried residues), and an absence of buried voids.

By the way, don't feel bad about giving feedback without having a chemistry background -- it's exactly what we're looking for. The whole point is to try to figure out how to make protein design accessible to everyone, and to harness the skills that regular gamers have who have not necessarily spent years studying biology or chemistry. We definitely appreciate your feedback, regardless your background!

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You can move separate pieces in chunks

In the selection interface. It is a recent addition and thanks again to jflat!
I enjoyed this puzzle style.

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