To search this landscape, Rosetta uses a combination of stochastic and deterministic algorithms: rebuilding all or a portion of the chain from fragments, random perturbation to a subset of the backbone torsion angles, combinatorial optimization of protein sidechain conformations, gradient based energy minimization, and energy-dependent acceptance or rejection of structure changes vi, vii, viii. The state-of-the-art Rosetta structure prediction methodology, for example, is limited primarily by conformational sampling the native structure almost always has lower energy than any non-native conformation, but the free energy landscape that must be searched is extremely large-even small proteins have on the order of 1000 degrees of freedom-and rugged due to unfavorable atom-atom repulsion which can dominate the energy even quite close to the native state. While it has been known for over 40 years that the three dimensional structures of proteins are determined by their amino acid sequences v, protein structure prediction remains a largely unsolved problem for all but the smallest protein domains. The integration of human visual problem-solving and strategy development capabilities with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems. Players working collaboratively develop a rich assortment of new strategies and algorithms unlike computational approaches, they explore not only conformational space but also the space of possible search strategies. We show that top Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve burial of hydrophobic residues. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology iv, while they compete and collaborate to optimize the computed energy. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Protein structure prediction is one such problem: locating the biologically relevant native conformation of a protein is a formidable computational challenge given the very large size of the search space. Simple image- and text-recognition tasks have been successfully crowd-sourced through games i, ii, iii, but it is not clear if more complex scientific problems can be similarly solved with human-directed computing. People exert significant amounts of problem solving effort playing computer games.
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