Foldit is an

online In computer technology and telecommunications, online indicates a state of connectivity and offline indicates a disconnected state. In modern terminology, this usually refers to an Internet connection, but (especially when expressed "on line" or ...

puzzle video game Puzzle video games make up a broad genre of video games that emphasize puzzle solving. The types of puzzles can test problem-solving skills, including logic, pattern recognition, sequence solving, spatial recognition, and word completion. H ...

about

protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...

. It is part of an experimental research project developed by the

University of Washington The University of Washington (UW, simply Washington, or informally U-Dub) is a public research university in Seattle, Washington. Founded in 1861, Washington is one of the oldest universities on the West Coast; it was established in Seattle a ...

, Center for Game Science, in collaboration with the UW Department of

Biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...

. The objective of Foldit is to fold the structures of selected

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s as perfectly as possible, using tools provided in the game. The highest scoring solutions are analyzed by researchers, who determine whether or not there is a native structural configuration (

native state In biochemistry, the native state of a protein or nucleic acid is its properly folded and/or assembled form, which is operative and functional. The native state of a biomolecule may possess all four levels of biomolecular structure, with the s ...

) that can be applied to relevant proteins in the real world. Scientists can then use these solutions to target and eradicate

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

s and create biological innovations. A 2010 paper in the science journal ''

Nature Nature, in the broadest sense, is the physics, physical world or universe. "Nature" can refer to the phenomenon, phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. ...

'' credited Foldit's 57,000 players with providing useful results that matched or outperformed algorithmically computed solutions.

History

Rosetta

Prof. David Baker, a protein research scientist at the University of Washington, founded the Foldit project. Seth Cooper was the lead game designer. Before starting the project, Baker and his laboratory coworkers relied on another research project named Rosetta to predict the native structures of various proteins using special computer

protein structure prediction Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is different ...

algorithm In mathematics and computer science, an algorithm () is a finite sequence of rigorous instructions, typically used to solve a class of specific Computational problem, problems or to perform a computation. Algorithms are used as specificat ...

s. Rosetta was eventually extended to use the power of

distributed computing A distributed system is a system whose components are located on different computer network, networked computers, which communicate and coordinate their actions by message passing, passing messages to one another from any system. Distributed com ...

: The

Rosetta@home Rosetta@home is a volunteer computing project researching protein structure prediction on the Berkeley Open Infrastructure for Network Computing (BOINC) platform, run by the Baker laboratory at the University of Washington. Rosetta@home aims ...

program was made available for public

download In computer networks, download means to ''receive'' data from a remote system, typically a server such as a web server, an FTP server, an email server, or other similar system. This contrasts with uploading, where data is ''sent to'' a remote s ...

, and displayed its protein-folding progress as a

screensaver A screensaver (or screen saver) is a computer program that blanks the display screen or fills it with moving images or patterns when the computer has been idle for a designated time. The original purpose of screensavers was to prevent phosphor ...

. Its results were sent to a central

server Server may refer to: Computing *Server (computing), a computer program or a device that provides functionality for other programs or devices, called clients Role * Waiting staff, those who work at a restaurant or a bar attending customers and su ...

for verification.

Howard Hughes Medical Institute The Howard Hughes Medical Institute (HHMI) is an American non-profit medical research organization based in Chevy Chase, Maryland. It was founded in 1953 by Howard Hughes, an American business magnate, investor, record-setting pilot, engineer, fil ...

br>"Protein-folding game taps power of worldwide audience to solve difficult puzzles"

Eurekalert! The American Association for the Advancement of Science (AAAS) is an American international non-profit organization with the stated goals of promoting cooperation among scientists, defending scientific freedom, encouraging scientific respons ...

, August 4, 2010 Some Rosetta@home users became frustrated when they saw ways to solve

protein structure Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer ma ...

s, but could not interact with the program. Hoping that humans could improve the computers' attempts to solve protein structures, Baker approached

David Salesin David Salesin is an American computer scientist. He has worked in computer graphics, three-dimensional and four-dimensional mathematics, and photorealistic rendering. Until 2019, he was the Director of Snap Inc. Research Team, an affiliate p ...

and Zoran Popović, computer science professors at the same university, to help conceptualize and build an interactive program, a

video game Video games, also known as computer games, are electronic games that involves interaction with a user interface or input device such as a joystick, controller, keyboard, or motion sensing device to generate visual feedback. This fee ...

, that would appeal to the public and help efforts to find native protein structures.

Foldit

Many of the same people who created Rosetta@home worked on Foldit. The public

beta Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiod ...

version was released in May 2008 and has 240,000 registered players. Since 2008, Foldit has participated in Critical Assessment of Techniques for Protein Structure Prediction (

CASP Critical Assessment of Structure Prediction (CASP), sometimes called Critical Assessment of Protein Structure Prediction, is a community-wide, worldwide experiment for protein structure prediction taking place every two years since 1994. CASP prov ...

) experiments, submitting its best solutions to targets based on unknown protein structures. CASP is an international program to assess methods of protein structure prediction and identify those that are most productive.

Goals

Protein structure prediction is important in several fields of science, including

bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...

molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...

, and

medicine Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pract ...

. Identifying natural proteins' structural configurations enables scientists to understand them better. This can lead to creating novel proteins by design, advances in treating disease, and solutions for other real-world problems such as

invasive species An invasive species otherwise known as an alien is an introduced organism that becomes overpopulated and harms its new environment. Although most introduced species are neutral or beneficial with respect to other species, invasive species ad ...

waste Waste (or wastes) are unwanted or unusable materials. Waste is any substance discarded after primary use, or is worthless, defective and of no use. A by-product, by contrast is a joint product of relatively minor economic value. A waste prod ...

, and

pollution Pollution is the introduction of contaminants into the natural environment that cause adverse change. Pollution can take the form of any substance (solid, liquid, or gas) or energy (such as radioactivity, heat, sound, or light). Pollutants, the ...

. The process by which living beings create the primary structure of proteins,

protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...

, is reasonably well understood, as is the means by which proteins are encoded as DNA. However, determining how a given protein's primary structure becomes a functioning three-dimensional structure, how the

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

''folds'', is more difficult. The general process is understood, but predicting a protein's eventual, functioning structure is

computation Computation is any type of arithmetic or non-arithmetic calculation that follows a well-defined model (e.g., an algorithm). Mechanical or electronic devices (or, historically, people) that perform computations are known as ''computers''. An es ...

ally demanding.

Methods

Similarly to Rosetta@home, Foldit is a means to discover native protein structures faster through distributed computing. However, Foldit has a greater emphasis on community collaboration through its forums, where users can collaborate on certain folds. Furthermore, Foldit's crowdsourced approach places a greater emphasis on the user. Foldit's virtual interaction and gamification create a unique and innovative environment with the potential to greatly advance protein folding research.

Virtual interaction

Foldit attempts to apply the

human brain The human brain is the central organ of the human nervous system, and with the spinal cord makes up the central nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. It controls most of the activities of the ...

's three-dimensional

pattern matching In computer science, pattern matching is the act of checking a given sequence of tokens for the presence of the constituents of some pattern. In contrast to pattern recognition, the match usually has to be exact: "either it will or will not be ...

and

spatial reasoning Spatial may refer to: *Dimension *Space *Three-dimensional space Three-dimensional space (also: 3D space, 3-space or, rarely, tri-dimensional space) is a geometric setting in which three values (called ''parameters'') are required to determ ...

abilities to help solve the problem of protein structure prediction. 2016 puzzles are based on well-understood proteins. By analysing how humans intuitively approach these puzzles, researchers hope to improve the algorithms used by protein-folding software. Foldit includes a series of

tutorial A tutorial, in education, is a method of transferring knowledge and may be used as a part of a learning process. More interactive and specific than a book or a lecture, a tutorial seeks to teach by example and supply the information to complete ...

s where users manipulate simple protein-like structures and a periodically updated set of puzzles based on real proteins. It shows a graphical representation of each protein which users can manipulate using a set of tools.

Gamification

Foldit's developers wanted to attract as many people as possible to the cause of protein folding. So, rather than only building a useful science tool, they used

gamification Gamification is the strategic attempt to enhance systems, services, organizations, and activities by creating similar experiences to those experienced when playing games in order to motivate and engage users. This is generally accomplished thro ...

(the inclusion of gaming elements) to make Foldit appealing and engaging to the general public. As a protein structure is modified, a ''score'' is calculated based on how well-folded the protein is, and a list of high scores for each puzzle is maintained. Foldit users may create and join groups, and members of groups can share puzzle solutions. Groups have been found to be useful in training new players. A separate list of group high scores is maintained.

Accomplishments

Results from Foldit have been included in a number of scientific publications. Foldit players have been cited collectively as "Foldit players" or "Players, F." in some cases. Individual players have also been listed as authors on at least one paper, and on four related

Protein Data Bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, cry ...

depositions. *An August 2010 paper in the journal ''

'' credited Foldit's 57,000 players with providing useful results that matched or outperformed algorithmically computed solutions, stating " ayers 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". *A November 2011 article in ''

PNAS ''Proceedings of the National Academy of Sciences of the United States of America'' (often abbreviated ''PNAS'' or ''PNAS USA'') is a peer-reviewed multidisciplinary scientific journal. It is the official journal of the National Academy of Scien ...

'' compared "recipes" developed by Foldit players to Rosetta scripts developed by members of the Baker Lab at the University of Washington. The player-developed "Blue Fuse" recipe compared favorably with the scientists' "Fast Relax" algorithm. *In 2011, Foldit players helped decipher the

crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystal, crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric pat ...

of a

retroviral A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptas ...

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

from

Mason-Pfizer monkey virus ''Mason-Pfizer monkey virus (M-PMV)'', formerly Simian retrovirus (SRV), is a species of retroviruses that usually infect and cause a fatal immune deficiency in Asian macaques. The ssRNA virus appears sporadically in mammary carcinoma of captiv ...

(M-PMV), a monkey

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

which causes

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

-like symptoms, a scientific problem that had been unsolved for 15 years. While the puzzle was available for three weeks, players produced a 3D model of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

in only ten days that is accurate enough for

molecular replacement Molecular replacement (or MR) is a method of solving the phase problem in X-ray crystallography. MR relies upon the existence of a previously solved protein structure which is similar to our unknown structure from which the diffraction data is de ...

. *In January 2012, ''

Scientific American ''Scientific American'', informally abbreviated ''SciAm'' or sometimes ''SA'', is an American popular science magazine. Many famous scientists, including Albert Einstein and Nikola Tesla, have contributed articles to it. In print since 1845, it i ...

'' reported that Foldit gamers achieved the first crowdsourced redesign of a protein, an

that catalysed the

Diels–Alder reaction In organic chemistry, the Diels–Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene derivative. It is the prototypical example of a peric ...

s widely used in

synthetic chemistry As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In mod ...

. A team including David Baker in the Center for Game Science at

Seattle Seattle ( ) is a seaport city on the West Coast of the United States. It is the seat of King County, Washington. With a 2020 population of 737,015, it is the largest city in both the state of Washington and the Pacific Northwest regio ...

computationally designed the enzyme from scratch but found its potency needed improvement. Foldit players reengineered the enzyme by adding 13

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s, increasing its activity by more than 18 times. *A September 2016 article in ''

Nature Communications ''Nature Communications'' is a peer-reviewed, open access, scientific journal published by Nature Portfolio since 2010. It is a multidisciplinary journal and it covers the natural sciences, including physics, chemistry, earth sciences, medicine, ...

'' detailed a "crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms" in which "a team of Foldit players achieved the most accurate structure" fitting a protein to the results of an

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

experiment. *A July 2018 article in ''

'' reviewed the collaboration between Foldit players and teams in the WeFold consortium in biennial

competitions CASP11 and CASP12. *A June 2019 letter in ''

'' described the analysis of proteins designed by Foldit players. Four player-designed proteins were successfully grown in ''

E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

'' and then "solved" via

. The proteins were added to the

a
6MRR6MRS6MSP
an
6NUK
*In November 2019, an article in ''

PLOS Biology ''PLOS Biology'' is a monthly peer-reviewed scientific journal covering all aspects of biology. Publication began on October 13, 2003. It is the first journal published by the Public Library of Science. The editor-in-chief is Nonia Pariente. In ad ...

'' reported how Foldit players were able to "build protein structures into crystallographic, high-resolution maps more accurately than expert crystallographers or automated model-building algorithms" using data from cryo EM experiments.

Future development

Foldit's toolbox is mainly for the design of protein molecules. The game's creator announced the plan to add, by 2013, the chemical building blocks of organic subcomponents to enable players to design small molecules.

References

External links

official Foldit website
{{Authority control 2008 video games Linux games MacOS games Windows games Puzzle video games Human-based computation games Lua (programming language)-scripted video games Structural bioinformatics software Computational biology Molecular biology Protein folding Protein structure Gamification Video games developed in the United States