Figure 2. Comparison of Foldit player and automated design sampling strategies.

a, Single trajectories (ignoring abandoned branches) for three Foldit player-designed proteins in red (Foldit1), blue (Peak6), and green (Ferredog-Diesel); and design trajectories for four Rosetta-designed proteins in gray. The y-axis is the Rosetta energy rescaled so that the final design has a value of −1.00, and positive energies are shown as zero. Foldit players are willing to undergo large increases in energy to explore new regions; the Rosetta protocol in contrast has a limited ability to escape local energy minima. Red circles correspond to structures shown in (b). b, Snapshots from the design trajectory of Foldit1: (i) the initial extended chain of poly-isoleucine; (ii) development of secondary structure; (iii) development of folded tertiary structure; (iv) sequence design of folded structure, with inset showing favorable packing at positions 13 and 45; (v) high-energy intermediate design, with inset showing redesign at positions 13 and 45, which results in steric clashes with the protein backbone; (vi) the final refined design, with inset showing renewed favorable interactions at positions 13 and 45. c, The design strategy for Foldit1 represented as a graph, showing all branch points where multiple design trajectories were spawned from a single intermediate. The final design was reached after 17 branch points. Node colors correspond to five different cooperating Foldit players, and the final design is marked as a star. d, Similar representation of a Rosetta design trajectory; there are only two branch points.