Principles for designing proteins with cavities formed by curved β sheets. The coming of age of de novo protein design. Control over overall shape and size in de novo designed proteins.
The genetic control of tertiary protein structure: studies with model systems. Predicting protein structures with a multiplayer online game. RNA design rules from a massive open laboratory. Phylo: a citizen science approach for improving multiple sequence alignment. Space-time wiring specificity supports direction selectivity in the retina. Galaxy Zoo: morphologies derived from visual inspection of galaxies from the Sloan Digital Sky Survey. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem. High-resolution structures were determined for four of the designs, and are nearly identical to the player models.
The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds-including a new fold not observed in natural proteins. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now-starting from an extended polypeptide chain-generate a diversity of protein structures and sequences that encode them in silico. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. We posed the challenge of de novo protein design in the online protein-folding game Foldit 5. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. An exception is the game EteRNA 4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson–Crick base pairing possibilities. Online citizen science projects such as GalaxyZoo 1, Eyewire 2 and Phylo 3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity.
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