Your de novo protein designs are looking extremely good! Our goal since we introduced design puzzles was to have the best solutions go straight into experimental testing. This requires synthesizing a gene encoding the design, putting the gene into bacteria to direct them to make the protein, and then purifying the designed protein away from everything else in the bacteria and determining whether it folds up the way you designed it to. As you can imagine, this involves a fair amount of effort, and up until recently there have been issues with the top scoring designs that would have had to be fixed before ordering the genes.

What are the issues that we would like to resolve before ordering your designs? There are several “rules of thumb” about proteins that earlier designs were not consistent with. The main one is very simple and familiar to most of you-in proteins the buried residues should be hydrophobic and the exposed residues should be polar. Another perhaps less familiar one is that glycine residues, which are very flexible, should only be in turns and loops, not in helices or sheets. Finally, there should be few alanine residues in the core because they are too small to stabilize the protein much.

The filters which have been added over the past month or two simply enforce the above rules. You might wonder why the score function itself doesn’t take care of these problems. The answer is that naturally occurring proteins break all the rules some of the time-nature had 3 billion years to fine tune things and can get away with things that designers simply can’t. If we encoded the rules directly in the score function, we would fail to correctly predict the structures of many native proteins.

The exciting result is that the top designs now do not break the rules, and so are close to being ready to order. On the other hand, there are clearly problems with the filters that make the game less fun to play, and we are working hard to fix them. The main issue is that they are slow to compute, but I think this can be fixed pretty easily (the way we are determining whether a residue is buried is more time consuming than it needs to be, for example).

So please keep designing, and we will work hard to improve speed. I’m really excited about the beautiful symmetric structures you are creating and can’t wait to start testing them. If the sequences of your designs fold up to the structures you have created it will be a major scientific milestone! There will be immediate applications, for example to stabilizing the HIV surface protein, which is a trimer, in a form which can be used as a vaccine.