How Gamers Are Contributing to Scientific Research on Protein Structures

When thinking about science one imagines people with white lab coats or even Indiana Jones style field scientist, but surely not just ordinary people playing a video game that helped writing of multiple scientific papers to the point the players was named as one of the authors of these papers as “Foldit Players” or “Player, F”! That’s right, there is a puzzle themed video game called Foldit which is described as “an online puzzle video game about protein folding”.

It all started in the University of Washington Department of Biochemistry as an experimental research project. The conventional way of solving secondary or tertiary protein structures are expensive, frustrating and therefore long processes such as x-ray crystallography that needs the scientist to be able to crystallize the protein -which if too large, has to work with subunits- and use equipment such as Synchrotron which is a specific type of cyclic particle accelerator just to collect data from these crystals, and finally to analyze these data sets to produce a meaningful result that is the structure of the protein of interest. Prof. David Baker, to tackle this issue with the technology at hand, have developed a program called Rosetta to predict structures. The technology at hand was the supercomputer that runs a program to calculate and search in large-scale for the most stable structure of proteins. The intensity of these queries resulted in the alternative version of the program called Rosetta@home which was available to distribute it to the personal computers and essentially was a screensaver! This version however had its own issues that people started giving feedback that the program was attempting at nonsense tries when folding and the users were completely unable to interact as the professor says, "People saw that Rosetta was making obvious mistakes, and they were getting frustrated that they couldn't manipulate the proteins themselves.".

Seeing that the people participating can see the mistakes in the program, the researchers set a secret race between the program and the users or gamers to solidify the idea that these users were better in this task than the program. And indeed, 8 out of 10 tests showed better if not worse results from user-controlled folding exercises as these pro-gamers were able to spot gaps in a folding protein that otherwise should be complemented with the side chains. With Prof. Baker’s words “There's this class of problems where a residue should be sticking into the core of the protein, but it isn't, it's sticking out, Rosetta moving that residue at random is not going to stick it into the core of the protein. But people can look at the protein, see that there's a hole, look at the side chain, see that it's sticking out, and put it in the right place. They're very good at that type of problem."

Since its inception Foldit contributed to solving the unknown protein structures under Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiments, an international program to evaluate methods of protein structure prediction and to decide the most fruitful ones. With the program gamifying and virtualizing the interactions of folding a protein, the community forums were active with users who would cooperate on difficult proteins who would reach a population of 250 thousand people! Foldit takes advantage of the 3D pattern matching, special awareness and the sense of competition and achievement of the human brain. Gamers collect points on their folding performance. The UI is easy to understand with minimal technicality and gives a tutorial with well known protein structures to teach the users. 57 thousand of these gamers ended up producing more valuable results than computer-based solutions resulting in being credited in Nature in 2010. With artificial intelligence in the spotlight, one can only guess where this machine vs human challenge will end up in future, but it is fair to say that science will make the most of it as seen in the story of Foldit.

Reference:
https://www.eurekalert.org/news-releases/816532
Koepnick B, Flatten J, Husain T, Ford A, Silva DA, Bick MJ, Bauer A, Liu G, Ishida Y, Boykov A, Estep RD, Kleinfelter S, Nørgård-Solano T, Wei L, Players F, Montelione GT, DiMaio F, Popović Z, Khatib F, Cooper S, Baker D. De novo protein design by citizen scientists. Nature. 2019 Jun;570(7761):390-394. doi: 10.1038/s41586-019-1274-4. Epub 2019 Jun 5. PMID: 31168091; PMCID: PMC6701466.
Cooper S, Khatib F, Treuille A, Barbero J, Lee J, Beenen M, Leaver-Fay A, Baker D, Popović Z, Players F. Predicting protein structures with a multiplayer online game. Nature. 2010 Aug 5;466(7307):756-60. doi: 10.1038/nature09304. PMID: 20686574; PMCID: PMC2956414.
https://fold.it/about_foldit