Seth Cooper

Predicting protein structures with a multiplayer online game

People exert large amounts of problem-solving effort playing computer games. Simple image- and text-recognition tasks have been successfully ‘crowd-sourced’ through games, but it is not clear if more complex scientific problems can be solved with human-directed computing. 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. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology, while they compete and collaborate to optimize the computed energy. We show that top-ranked Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop a rich assortment of new strategies and algorithms; unlike computational approaches, they explore not only the conformational space but also the space of possible search strategies. 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.

Rosetta3: An Object-Oriented Software Suite for the Simulation and Design of Macromolecules

We have recently completed a full re-architecturing of the ROSETTA molecular modeling program, generalizing and expanding its existing functionality. The new architecture enables the rapid prototyping of novel protocols by providing easy-to-use interfaces to powerful tools for molecular modeling. The source code of this rearchitecturing has been released as ROSETTA3 and is freely available for academic use. At the time of its release, it contained 470,000 lines of code. Counting currently unpublished protocols at the time of this writing, the source includes 1,285,000 lines. Its rapid growth is a testament to its ease of use. This chapter describes the requirements for our new architecture, justifies the design decisions, sketches out central classes, and highlights a few of the common tasks that the new software can perform.

Continuum crowds

We present a real-time crowd model based on continuum dynamics. In our model, a dynamic potential field simultaneously integrates global navigation with moving obstacles such as other people, efficiently solving for the motion of large crowds without the need for explicit collision avoidance. Simulations created with our system run at interactive rates, demonstrate smooth flow under a variety of conditions, and naturally exhibit emergent phenomena that have been observed in real crowds.

Crystal structure of a monomeric retroviral protease solved by protein folding game players

Following the failure of a wide range of attempts to solve the crystal structure of M-PMV retroviral protease by molecular replacement, we challenged players of the protein folding game Foldit to produce accurate models of the protein. Remarkably, Foldit players were able to generate models of sufficient quality for successful molecular replacement and subsequent structure determination. The refined structure provides new insights for the design of antiretroviral drugs.

Algorithm discovery by protein folding game players

Foldit is a multiplayer online game in which players collaborate and compete to create accurate protein structure models. For specific hard problems, Foldit player solutions can in some cases outperform state-of-the-art computational methods. However, very little is known about how collaborative gameplay produces these results and whether Foldit player strategies can be formalized and structured so that they can be used by computers. To determine whether high performing player strategies could be collectively codified, we augmented the Foldit gameplay mechanics with tools for players to encode their folding strategies as “recipes” and to share their recipes with other players, who are able to further modify and redistribute them. Here we describe the rapid social evolution of player-developed folding algorithms that took place in the year following the introduction of these tools. Players developed over 5,400 different recipes, both by creating new algorithms and by modifying and recombining successful recipes developed by other players. The most successful recipes rapidly spread through the Foldit player population, and two of the recipes became particularly dominant. Examination of the algorithms encoded in these two recipes revealed a striking similarity to an unpublished algorithm developed by scientists over the same period. Benchmark calculations show that the new algorithm independently discovered by scientists and by Foldit players outperforms previously published methods. Thus, online scientific game frameworks have the potential not only to solve hard scientific problems, but also to discover and formalize effective new strategies and algorithms.

Increased Diels-Alderase activity through backbone remodeling guided by Foldit players

Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes. Here we report the use of game-driven crowdsourcing to enhance the activity of a computationally designed enzyme through the functional remodeling of its structure. Players of the online game Foldit were challenged to remodel the backbone of a computationally designed bimolecular Diels-Alderase to enable additional interactions with substrates. Several iterations of design and characterization generated a 24-residue helix-turn-helix motif, including a 13-residue insertion, that increased enzyme activity >18-fold. X-ray crystallography showed that the large insertion adopts a helix-turn-helix structure positioned as in the Foldit model. These results demonstrate that human creativity can extend beyond the macroscopic challenges encountered in everyday life to molecular-scale design problems.Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes. Here we report the use of game-driven crowdsourcing to enhance the activity of a computationally designed enzyme through the functional remodeling of its structure. Players of the online game Foldit were challenged to remodel the backbone of a computationally designed bimolecular Diels-Alderase to enable additional interactions with substrates. Several iterations of design and characterization generated a 24-residue helix-turn-helix motif, including a 13-residue insertion, that increased enzyme activity >18-fold. X-ray crystallography showed that the large insertion adopts a helix-turn-helix structure positioned as in the Foldit model. These results demonstrate that human creativity can extend beyond the macroscopic challenges encountered in everyday life to molecular-scale design problems.

The challenge of designing scientific discovery games

Incorporating the individual and collective problem solving skills of non-experts into the scientific discovery process could potentially accelerate the advancement of science. This paper discusses the design process used for Foldit, a multiplayer online biochemistry game that presents players with computationally difficult protein folding problems in the form of puzzles, allowing ordinary players to gain expertise and help solve these problems. The principle challenge of designing such scientific discovery games is harnessing the enormous collective problem-solving potential of the game playing population, who have not been previously introduced to the specific problem, or, often, the entire scientific discipline. To address this challenge, we took an iterative approach to designing the game, incorporating feedback from players and biochemical experts alike. Feedback was gathered both before and after releasing the game, to create the rules, interactions, and visualizations in Foldit that maximize contributions from game players. We present several examples of how this approach guided the games design, and allowed us to improve both the quality of the gameplay and the application of player problem-solving.

The impact of tutorials on games of varying complexity

One of the key challenges of video game design is teaching new players how to play. Although game developers frequently use tutorials to teach game mechanics, little is known about how tutorials affect game learnability and player engagement. Seeking to estimate this value, we implemented eight tutorial designs in three video games of varying complexity and evaluated their effects on player engagement and retention. The results of our multivariate study of over 45,000 players show that the usefulness of tutorials depends greatly on game complexity. Although tutorials increased play time by as much as 29% in the most complex game, they did not significantly improve player engagement in the two simpler games. Our results suggest that investment in tutorials may not be justified for games with mechanics that can be discovered through experimentation.

Active learning for real-time motion controllers

This paper describes an approach to building real-time highly-controllable characters. A kinematic character controller is built on-the-fly during a capture session, and updated after each new motion clip is acquired. Active learning is used to identify which motion sequence the user should perform next, in order to improve the quality and responsiveness of the controller. Because motion clips are selected adaptively, we avoid the difficulty of manually determining which ones to capture, and can build complex controllers from scratch while significantly reducing the number of necessary motion samples.

On the harmfulness of secondary game objectives

Secondary game objectives, optional challenges that players can choose to pursue or ignore, are a fundamental element of game design. Still, little is known about how secondary objectives affect player behavior. It is commonly believed that secondary objectives such as coins or collectible items can increase a games flexibility, replayability, and depth. In contrast, we present results from analysis of two popular online Flash games showing that secondary objectives can easily harm the retention of many players. We support our findings with data collected from over 27,000 players through large-scale A/B tests in which we measured play time, progress, and return rate. We show that while secondary objectives can encourage long-term players to extend their playtime, they can also cause many players to play for less time. By modifying secondary objectives so that they reinforce the primary goal of the game instead of distracting from it, we are able to avoid negative consequences and still maintain the retention of long-term players. Our results suggest that secondary objectives that support the primary goal of the game are consistently useful, while secondary objectives that do not support the main goal require extensive testing to avoid negative consequences.