DockIt: Development and launch of a crowd-sourced serious-games platform for protein docking for use by the public and the scientific community.

AIM - The aim of this grant is to develop a serious and enjoyable computer game (DockIt) used by numerous players (a crowd) to model how two large biological molecules (proteins) fit together and thereby perform their function.

PROTEIN DOCKING: AN UNSOLVED BIOLOGICAL PROBLEM - Proteins are large biological molecules, generally with at least 1,000 atoms, which perform many biological functions. The three-dimensional structure of a protein is complex. Central to its biological activity is that often it docks to another protein to form a complex. The structure of the complex is dictated by how the atoms in the molecules interact with each other. The shape of the complex helps in understanding the mechanism of action of proteins and this knowledge can have major benefits in food security, industrial biotechnology and the design of novel pharmaceuticals. Computational approaches are used to predict the shape of a complex given knowledge of the structures of the unbound components. However the programs have only limited success. Research in other areas of science, including modelling the shape of proteins, has shown that individuals using human judgement can sometimes find solutions to problems that cannot yet be solved automatically. In particular finding consensus solutions from a crowd of players can yield successful results. This approach is known as crowd sourcing. Accordingly, we propose to develop a computer game DockIt where the players will manipulate the two protein structures and predict a complex. This is similar to solving a three-dimensional jigsaw puzzle. The docking will start with a set of possible complexes generated by state of the art programs and thus successful plays can yield predicted structures superior to those automatically generated.

THE DOCKIT GAME - We will design DockIt so that it is fun to play by exploiting the latest technology and design from the casual games industry. We will develop DockIt for a range of platforms including tablets, smartphones and PCs thereby ensuring wide take-up. A user will be able to adjust the relative position of the two proteins and to change the shape of each protein. The approaches to alter the proteins will be encoded as a set of recipes which the user can employ. We will provide a scoring function to feedback to the players an estimate of the quality of the predicted structure.

RELEASE OF DOCKIT - We will release DockIt for use by the academic community and to the general public. Our strategy to publicise DockIt is to work with our partners, collaborators and industry contacts to promote DockIt via their extensive player databases, for example by inclusion in newsletters. The docking targets will include those for which the solution is known and those where DockIt is used to solve a real-world biological problem. Players will download a possible complex from the host server and then change its shape to predict the best complex which will then be returned to the server. Results from different players will be pooled and we will identify the best prediction. Players will be supported by the presence of a tutorial which will provide progressive steps to learn the game. There will be E-mail support and a social network group will be established (e.g. Google+, FaceBook, LinkedIn and Twitter).

DISSEMINATION - DockIt will be disseminated to the scientific community and the general public. We will make presentations at scientific conferences and publish technical papers. We will issue a press release aimed at the games together with popular science magazines. We will also target TV, Radio, the educational press and trade bodies. We envisage that DockIt could be used at schools and universities in teaching.

The aim is to develop, launch and publicise DockIt, a crowd-sourced serious-games platform for protein docking for use by the public and the scientific community.

The procedure will start from the known structures of two unbound molecules and the fact that they dock. We will start with a pool of models generated by leading-edge docking servers. Regions of backbone flexibility will be identified by normal mode analysis. In addition, from the literature, we will identify residues at the interface. The docking score will be a combination of the stereochemical quality and the number of satisfied distance constraints.

The user interface will target the touch paradigm allowing the user to play the game on tablets and smartphones (iOS, Windows8 and Android), and on PCs. There will be a seamless interface encompassing rigid body, conformational change and zoom. The paradigm from the art package Z-brush will be used for selection and manipulation in 3D. We will develop methods to perform rigid-body shifts and to alter backbone and side-chains. Players will be provided with visual and audio cues for favourable and unfavourable interactions. A format will be developed for games analytics, possibly using waypoints.

A DockIt web site will be provided for player registration and game client download. Docking targets will be graded by difficulty. Players will submit solutions which will be stored on our DockIt server. Each solution submitted to the DockIt server will automatically be accompanied by the sequence of moves including the recipes used by the player. Players' solutions will be scored in terms of match to the correct solution when known. For unknown targets the energy function and the number of distance constraints satisfied will be used as a score. High score tables will be provided. DockIt will be tested in the international blind trial CAPRI and used to suggest complexes for proteins of interest to the community.

PROJECT AIM - The aim is to develop, launch and publicise DockIt, a crowd-sourced serious-games platform for protein docking for use by the public and the scientific community. DockIt will be used to solve the challenging problem of protein docking incorporating flexibility and residue specific information. Evidence from several scientific areas has shown that manual insight can deliver accurate solutions that cannot be obtained by computation alone. The professional-quality game will be visually attractive, free to play and supported. DockIt will be launched to the public and users will be able to tackle real world problems on protein docking.

BIOSCIENCE INDUSTRY - Structural determination of the 3D structure of a protein-protein complex remains problematic. Many biologists working in the commercial sector require this information to understand the structure/function relations of the system they are studying. For example the functional effect of an amino-acid change to the protein such as a non-synonymous single nucleotide polymorphism (an nsSNP) could be explained in terms of its alteration of the protein-protein interaction. These can explain human and animal genetic disease. Knowledge of protein-protein interactions can guide the discovery of novel drugs. We will collect from the community complexes which are of biological interest and use DockIt to predict the complexes. The results will be made available to both academic and commercial researchers on our web site.

GAMES INDUSTRY - DockIt will advance the methodology to manipulate complex 3D objects in real time and this remains a challenging topic for the games industry in developing optimal human/computer interactions. This applied both for rigid bodies and even more so for flexible objects. DockIt will further methodology for graphical user interface (GUI) in the context of the touch paradigm. More generally there is the potential for the industry to identify a new market in serious scientific games.

GENERAL PUBLIC - DockIt will be played by the general public. Popular crowd-sourced scientific games have over 200,000 registered users and we aim to make DockIt popular. Our strategy is to employ methods from the games industry to make the program available on a range of platforms including tablets, mobile phones and PCs. We will engage with the general public by press releases. We envisage access to a large user base via UK games publishers (EA and Jagex). DockIt could be ported to Amazon for scalable mass market take up (possibly including sponsorship). Players will be supported by the presence of a tutorial which will provide progressive steps to learn the game. There will be E-mail support and a social network groups established (e.g. Google+, FaceBook, or similar). A major benefit will therefore by to excite the public to explore a scientific problem.

EDUCATION SECTOR - DockIt can serve as an educational tool in schools and universities to teach structural modelling in biology in particular and computer games in general. DockIt could be included in on-line mass market training courses (e.g. Coursera).

MUSEUMS - DockIt could readily be incorporated into museum displays. We will contact several leading museums nationally and internationally to draw their attention to DockIt.

PUBLIC POLICY AND GOVERNMENT - The UK is already a leading player in development of massively multiplayer on-line games (MMO) in traditional areas. This project will extend expertise into a new area for development and support of crowd sourced serious games. The computer games trade bodies (TIGA and UKIE) will therefore be interested in the project. Policy makers will value the new knowledge gained about the potential of serious gaming to involve the public in science. In particular, DockIt addresses some of the recommendation of the Livingstone Hope report on the use of video games and visual effects in education.