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Foldit

Foldit is a free online multiplayer puzzle video game developed by researchers at the University of Washington, in which players manipulate three-dimensional representations of proteins to predict their folded structures, thereby contributing to real-world scientific research in biochemistry and structural biology.^[1] Released on May 8, 2008, the game transforms the computationally intensive challenge of protein folding—essential for understanding diseases and designing drugs—into an accessible, competitive format that leverages human intuition for spatial reasoning over traditional algorithms.^[2] Built on the Rosetta software suite for protein modeling, Foldit provides tools for players to adjust amino acid chains, bury hydrophobic residues, and minimize energy scores, with puzzles ranging from introductory tutorials to advanced challenges submitted by scientists.^[1] Since its launch, Foldit has engaged over 240,000 registered players worldwide as of 2025, fostering a community of citizen scientists who collaborate and compete to solve protein structures that have stumped experts for years. Notable achievements include players determining the crystal structure of a monomeric retroviral protease from a simian AIDS-like virus in 2011, a problem unsolved for over a decade, which advanced understanding of viral enzymes and potential drug targets.^[3] The game has also enabled de novo protein design, with top players creating novel proteins that match or exceed computational methods in quality, as demonstrated in studies where Foldit solutions informed experimental validations.^[1] During the COVID-19 pandemic, Foldit puzzles focused on designing protein binders for the SARS-CoV-2 spike protein, yielding thousands of candidate structures for antiviral drug development.^[4] Foldit's impact extends beyond immediate discoveries, as player strategies have inspired improvements to protein prediction algorithms, and it serves as an educational platform for teaching molecular biology concepts through gamification. Foldit's lead developer, David Baker, was awarded half of the 2024 Nobel Prize in Chemistry for computational protein design.^[5]^[6] Available on Windows, macOS, and Linux, the game operates without requiring scientific expertise, yet its results are rigorously evaluated by researchers, highlighting the power of crowdsourcing in accelerating scientific progress.^[7]

Overview

Purpose

Foldit is an online puzzle video game developed by the University of Washington Center for Game Science in collaboration with the Baker Laboratory, designed to crowdsource solutions to the protein folding problem through player engagement.^[8] By transforming complex biochemical challenges into accessible gameplay, Foldit enables participants to manipulate virtual protein structures, contributing directly to scientific research without requiring prior expertise in biology or chemistry.^[9] The game builds on the Rosetta software suite for protein structure prediction, adapting its computational methods into an interactive format to harness collective human problem-solving.^[10] The protein folding problem refers to the process by which a protein's linear chain of amino acids spontaneously assembles into a functional three-dimensional structure, a phenomenon driven by physical and chemical interactions that determine the protein's native conformation.^[11] This folding is essential in biology, as a protein's 3D shape dictates its role in cellular processes such as enzymatic catalysis, signaling, and structural support.^[12] Misfolding can lead to debilitating diseases, including Alzheimer's, where aggregated proteins like amyloid-beta disrupt neuronal function, while accurate folding knowledge is critical for drug design, enabling the development of molecules that target specific protein conformations to treat conditions like cancer or infectious diseases.^[13]^[12] As a citizen science initiative, Foldit leverages the spatial reasoning and pattern recognition abilities of non-expert players to generate protein models that often surpass those produced by automated algorithms alone, demonstrating how human intuition can accelerate breakthroughs in structural biology.^[14] Players worldwide collaborate and compete to optimize protein folds, yielding insights that inform real-world research in areas like enzyme engineering and therapeutic development.^[15] Launched in public beta in May 2008, Foldit has attracted over 735,000 registered players as of 2019, fostering a global community that continues to advance biomedical discovery through gamified participation.^[16]

Gameplay Fundamentals

Foldit puzzles introduce players to protein folding through a series of structured challenges that build foundational skills. Introductory tutorials guide new users with simple tasks, such as folding basic alpha helices or beta sheets, using ribbon-like representations of protein backbones to teach core concepts without overwhelming complexity.^[1] These early puzzles emphasize achieving target scores by minimizing structural clashes and voids, providing immediate feedback on progress. As players advance, puzzles evolve into more sophisticated types, including refinement of experimentally determined structures where partial folds are adjusted for accuracy, and de novo design challenges that require creating novel protein sequences and conformations from scratch to meet specific objectives like symmetry or binding affinity.^[17]^[1] Player progression in Foldit is tiered to accommodate skill development, starting with beginner-level puzzles accessible after completing tutorials. These are designed for novices, featuring simplified models like ribbon backbones without side chains, and are limited to players with fewer than 150 global points earned from prior rankings.^[17] Upon gaining experience and points, players unlock intermediate and advanced puzzles, which involve complex manipulations including side chains for hydrophobic packing and ligands for molecular interactions, demanding precise control to optimize overall structure stability.^[1] This level-based system encourages gradual mastery, with global points accumulating based on puzzle performance to gate access and foster long-term engagement. At the heart of Foldit gameplay are intuitive core actions that allow direct interaction with protein models. Players rotate segments using tools like the tweak function to adjust helices or sheets rigidly, pull distant parts together with rubber bands to form bonds, and freeze selected segments to lock them in place during refinements, all aimed at minimizing energy and approximating native conformations.^[17]^[1] These manipulations are supplemented by automated aids, such as shaking for side-chain repacking, but emphasize manual intervention to explore conformational space effectively. Foldit supports both solo and collaborative play modes to suit different engagement styles. In solo mode, individuals tackle puzzles independently, competing against global leaderboards for personal rankings and points.^[1] Collaborative modes enable team-based efforts, where groups share structures via the server, iterate on solutions collectively, and participate in competitions with aggregated scores, enhancing motivation through social interaction.^[17]^[1]

Development History

Rosetta Foundations

The Rosetta project originated in the mid-1990s in the laboratory of David Baker at the University of Washington, where it was developed as a computational tool for ab initio protein structure prediction.^[18] The core algorithm employed a physics-based approach, assembling short polypeptide fragments—typically 3 or 9 residues long—derived from known protein structures in the Protein Data Bank, using a Monte Carlo sampling strategy to explore conformational space. These fragments were iteratively refined through energy minimization, guided by an all-atom potential function that accounted for van der Waals interactions, hydrogen bonding, solvation effects, and backbone torsional preferences, aiming to identify low-energy conformations resembling native folds. A pivotal expansion of the Rosetta framework came with the launch of Rosetta@home in June 2005, a volunteer-based distributed computing network built on the BOINC platform.^[19] This initiative harnessed idle computational resources from thousands of participants worldwide to perform large-scale simulations, enabling the prediction of protein structures, docking interactions, and de novo designs that would otherwise require immense supercomputing power.^[20] By crowdsourcing calculations, Rosetta@home significantly accelerated the sampling of vast conformational landscapes, contributing to advancements in understanding protein folding pathways and therapeutic targets.^[21] Despite these innovations, Rosetta faced inherent limitations due to its computational intensity, as exhaustive exploration of protein folding funnels often demanded prohibitive processing times, even with distributed resources.^[22] The algorithm struggled particularly with capturing non-local interactions, such as the dense packing of side chains in protein cores or the optimal alignment of distant secondary structure elements, where human spatial intuition could outperform automated sampling.^[23] These challenges highlighted the potential value of incorporating human problem-solving capabilities, ultimately inspiring the gamification of protein modeling. Early demonstrations of Rosetta's power in de novo protein design were exemplified by the 2003 creation of Top7, a 93-residue α/β protein engineered from scratch to adopt a novel fold not observed in nature.^[24] Using iterative cycles of sequence optimization and structure prediction, Baker's team designed Top7 with atomic accuracy, and its experimental validation via X-ray crystallography confirmed a backbone root-mean-square deviation of 1.2 Å from the computational model, marking a landmark in computational protein engineering.^[24] This work underscored Rosetta's role in enabling the rational design of functional proteins, laying groundwork for applications in biotechnology.^[24] Foldit later adapted Rosetta's core engine to leverage player ingenuity for overcoming these design hurdles.

Foldit Creation and Milestones

Foldit emerged from a collaborative effort in 2007–2008 between the University of Washington's Center for Game Science, directed by Zoran Popović, and the Department of Biochemistry, led by David Baker, to transform the computational protein structure prediction tool Rosetta into an accessible online game. This initiative sought to harness human spatial reasoning and pattern recognition skills to address challenges in protein folding that traditional algorithms struggled with, building directly on Rosetta as the underlying modeling engine.^[25]^[8]^[14] The public beta version launched in May 2008, marking the game's debut as a crowdsourced research platform and quickly drawing interest from gamers and scientists alike. Over its initial years, Foldit saw explosive growth, reaching 240,000 registered users by late 2011, which enabled the submission of approximately 600 player-generated protein structure predictions for scientific analysis.^[17]^[26] A pivotal milestone came in August 2010 with the publication of a study in Nature, which rigorously assessed Foldit player solutions against automated methods and found that non-expert participants often achieved superior results in predicting protein structures, particularly for challenging cases involving symmetric folds or novel topologies. This validation underscored Foldit's potential as a hybrid human-computational approach to biochemistry.^[27] The game's development benefited from substantial institutional backing, including grants from the National Science Foundation, the U.S. Defense Advanced Research Projects Agency, the Howard Hughes Medical Institute, and Microsoft, alongside sustained collaboration with the Baker Lab to incorporate advancements from Rosetta's algorithmic evolution. These resources facilitated ongoing refinements, ensuring Foldit's alignment with cutting-edge protein modeling techniques.^[14] Subsequent milestones include the introduction of Foldit Education Mode in 2020, a self-guided tutorial system for teaching protein biochemistry concepts to students and beginners.^[28] In August 2025, an updated web-based version (v2) was released, eliminating the need for downloads, improving puzzle interfaces, and enhancing accessibility.^[29]

Mechanics and Interface

Virtual Protein Manipulation

Foldit provides players with an intuitive 3D graphical interface for manipulating virtual protein structures, built upon the Rosetta molecular modeling suite. The visualization employs standard molecular graphics techniques, including ribbon diagrams to represent secondary structures such as alpha helices and beta sheets, backbone traces to outline the polypeptide chain, and toggleable side-chain displays for detailed atomic interactions. Players interact primarily through mouse-based controls, enabling direct dragging of protein segments to rotate bonds, adjust loop conformations, or reposition entire helices and sheets, facilitating rapid exploration of conformational space without requiring command-line inputs.^[30] Central to the manipulation toolkit are automated and semi-automated functions that assist in refining player adjustments. The Wiggle tool performs local optimization by iteratively minimizing steric clashes and energy penalties through small perturbations to backbone dihedral angles and side-chain rotamers, often applied after manual moves to polish structures. Complementing this, the Shake tool introduces random perturbations to disrupt local minima, allowing players to escape suboptimal configurations and explore alternative folds. For protein design puzzles, Blueprint mode enables sequence-level editing by visualizing the primary structure as a linear schematic and applying predefined secondary structure "building blocks," such as ideal loops or helices, to scaffold novel topologies.^[31]^[28] To manage structural complexity, Foldit scales visualizations and computations for proteins up to approximately 500 residues, beyond which performance may degrade, though larger assemblies can be loaded with reduced graphical detail. Symmetry tools support the modeling of oligomeric proteins, such as dimers or tetramers, by enforcing cyclic or dihedral symmetries during manipulation; players edit a single asymmetric unit (monomer), with changes automatically propagated to symmetric copies, streamlining the design of multimeric complexes.^[32] The platform has evolved from a standalone desktop application, initially released in 2008 for Windows and later expanded to Mac and Linux, to incorporate web-based access in recent years, particularly through Foldit Education Mode launched in 2020 and updated to version 2 in 2025. This web iteration broadens accessibility for educational use while retaining core manipulation features, allowing browser-based play without installations.^[28]^[29]

Scoring and Gamification

The scoring system in Foldit is derived from the Rosetta macromolecular modeling suite's energy function, which evaluates protein conformations by approximating their physical stability. Favorable low-energy states, such as hydrogen bonds between polar residues and van der Waals contacts that pack hydrophobic cores efficiently, contribute negatively to the total energy, thereby increasing the game's score. Conversely, unfavorable interactions like atomic clashes, where residues overlap sterically, incur positive penalties that decrease the score. The overall score is computed as the negative of the Rosetta energy (REF2015 or similar variants), so higher numerical values indicate more stable, native-like structures; a simplified representation is Total Score = −∑(favorable bond and contact energies) + clash and strain penalties.^[27]^[33] Gamification elements in Foldit motivate players through competitive and collaborative mechanics integrated with the scoring framework. Leaderboards rank participants by global points earned from puzzle completions, with separate categories for solo players, evolving teams, and groups, updated on weekly, monthly, and 120-day cycles to foster ongoing engagement. Achievements are awarded via puzzle milestones and strategy innovations, such as developing shareable "recipes" (automated scripts) that optimize folding paths, while "puzzles of the week" introduce timed challenges rewarding speed and novel solutions with bonus points. Team chats enable real-time discussion and strategy sharing, turning individual scores into collective progress on complex puzzles.^[31]^[34] Immediate feedback mechanisms enhance intuitive gameplay by providing dynamic guidance tied to the scoring system. Real-time score updates reflect structural changes as players manipulate the protein, allowing instant assessment of moves like loop adjustments or side-chain rotations. An undo function, including a graphical history of score fluctuations, lets users revert to previous states or the session's best conformation, reducing frustration and encouraging experimentation without permanent setbacks.^[30]^[35] These features exploit psychological drivers of motivation, where competition via leaderboards spurs rapid optimization, and collaboration through chats and shared recipes amplifies creative problem-solving. Players often devise folding strategies that surpass automated algorithms, leveraging spatial intuition and pattern recognition—human strengths that complement AI limitations in exploring non-local interactions. This blend of rivalry and cooperation has led to algorithmic discoveries, such as player-invented relaxation protocols akin to advanced computational methods, demonstrating how gamification harnesses collective ingenuity for scientific gains.^[31]

Scientific Applications

Protein Folding Goals

Foldit's primary goals in protein folding revolve around predicting the native three-dimensional structures of proteins, designing entirely novel proteins with desired functions, and remodeling existing proteins to enhance their utility in biomedical applications. These objectives leverage human intuition to tackle problems that remain computationally intensive, such as accurately sampling the vast conformational space of polypeptides to identify low-energy states. For instance, players contribute to de novo protein design by creating synthetic sequences that fold into stable, functional monomers.^[36] Similarly, remodeling efforts focus on modifying protein backbones and side chains to improve stability or introduce therapeutic properties, such as altered binding affinities for disease-related targets.^[1] The game specifically addresses hard-to-solve cases in protein folding, including membrane proteins embedded in lipid bilayers and those requiring cofactors like metal ions or heme groups for stability and function. These challenges arise from the rugged energy landscapes and environmental constraints that hinder traditional algorithms, such as the need to model hydrophobic interactions across membrane interfaces or cofactor coordination geometries. Foldit players excel in these scenarios by intuitively performing backbone rearrangements and loop optimizations that automated methods struggle with, often achieving lower root-mean-square deviation (RMSD) values compared to baseline Rosetta simulations.^[1] Recent developments incorporate hybrid approaches with artificial intelligence, where AlphaFold predictions are used to evaluate and provide bonuses for player designs, allowing refinement for improved accuracy on complex targets.^[37] Player-generated solutions form a critical data pipeline, where high-scoring models are periodically uploaded and processed through the Rosetta suite for energy minimization and all-atom refinement. These refined structures are then validated against experimental benchmarks, including nuclear magnetic resonance (NMR) spectroscopy for solution-state dynamics and cryo-electron microscopy (cryo-EM) for large assemblies, ensuring alignment with real-world data such as backbone dihedral angles or residue contacts. This iterative process has demonstrated superior performance in blind tests, with Foldit models resolving structures to within 1-2 Å RMSD in cases where Rosetta alone exceeded 4 Å.^[1]^[3] Beyond structure prediction, Foldit's contributions hold broader implications for accelerating drug discovery, particularly by elucidating protein binding sites that serve as targets for small-molecule therapeutics. Accurate models enable the identification of pockets or interfaces suitable for inhibitor design, as seen in efforts to target viral proteases where player insights revealed novel monomer conformations amenable to antiretroviral binding. This human-driven approach not only speeds up the validation of potential drug candidates but also informs rational modifications to enhance selectivity and efficacy in treating diseases like HIV or cancer.^[3] The game's scoring function acts as a proxy for biophysical realism, rewarding configurations that mimic native folding stability without delving into explicit force-field calculations.^[1]

Research Integration Methods

Player-generated protein models in Foldit are submitted automatically to the game's server during gameplay, typically every few minutes, allowing real-time tracking of progress on puzzles. Upon completion of a puzzle, the highest-scoring models from players are selected and processed through the Rosetta software suite for further validation. This involves energy minimization using protocols like FastRelax, which applies cycles of side-chain repacking and gradient-based minimization to refine the structure and lower the computed energy, ensuring physical realism. In some workflows, these refined models undergo additional molecular dynamics simulations to evaluate stability and dynamic behavior under simulated conditions.^[38]^[31]^[32] Foldit's collaboration model integrates player efforts directly into scientific research by basing puzzles on authentic problems, such as protein structure prediction targets from the Critical Assessment of Structure Prediction (CASP) competitions. During events like CASP9 and CASP11, Foldit teams incorporated player-optimized models into official submissions, often outperforming automated methods in specific targets. Feedback loops exist where top player solutions are analyzed by researchers, inspiring algorithm improvements in Rosetta and contributing to peer-reviewed publications that credit the Foldit community.^[39]^[40] Anonymized player contributions are shared publicly to advance structural biology, with refined models deposited into databases like the Protein Data Bank (PDB). These entries often include metadata linking back to the originating Foldit puzzle via unique identifiers, such as puzzle node numbers, enabling traceability without revealing player identities unless explicitly consented. For instance, de novo protein designs from Foldit players have resulted in dozens of novel proteins that folded as designed, with several structures experimentally validated and archived in the PDB (e.g., PDB IDs 6MSN, 6MSO, 6MSP, 6MSQ), supporting broader research on protein function and drug design.^[36] Recent extensions include small-molecule design capabilities, such as the 2025 Drugit mode, where players design non-peptidic binders for protein targets like VHL inhibitors, integrating with Rosetta for validation and potential therapeutic applications.^[41]

Accomplishments

Key Scientific Breakthroughs

One of the earliest demonstrations of Foldit's scientific value came in 2010, when over 57,000 players collectively contributed to protein structure predictions that matched or exceeded the performance of automated computational methods in challenging cases, as evaluated during the Critical Assessment of Structure Prediction (CASP9) experiment. This crowdsourced effort highlighted the potential of human intuition in refining protein models, particularly for targets where traditional algorithms struggled with complex topologies. The players' inputs, aggregated through the game's collaborative interface, led to the development of novel optimization strategies that improved prediction accuracy beyond existing tools like Rosetta's automated protocols.^[31] A landmark achievement occurred in 2011, when Foldit players resolved the crystal structure of a monomeric retroviral protease from Mason-Pfizer monkey virus (M-PMV), an unsolved problem that had persisted for over 15 years and held implications for understanding HIV-like viral maturation.^[42] Over a three-week period, approximately 240 players in the Foldit Void Crushers and Contenders groups iteratively refined models, generating structures accurate enough for molecular replacement and subsequent X-ray crystallography validation, where expert methods had previously failed.^[42] This breakthrough provided critical insights into protease dimerization inhibition, advancing potential strategies for antiretroviral drug design.^[42] In 2019, Foldit players achieved a milestone in de novo protein design by creating novel proteins from extended polypeptide chains, resulting in four experimentally validated structures deposited in the Protein Data Bank (PDB IDs: 6MRR, 6MRS, 6MSP, 6NUK), which closely matched the players' in silico models with Cα RMSD values of 0.9–1.7 Å.^[43] These designs, developed collaboratively by Foldit players, spanned 20 unique folds—including a novel one—and demonstrated high stability (some with folding free energies exceeding 20 kcal/mol), confirming the proteins' solubility and folded states via chromatography, circular dichroism, and high-resolution methods like X-ray and NMR.^[43] The diversity and stability of these citizen-designed proteins open avenues for therapeutic applications, such as customizable scaffolds for drug delivery or enzyme mimics.^[43] Foldit's early contributions also extended to enzyme redesign, exemplified by players' 2012 remodeling of a computationally designed Diels-Alderase, which increased catalytic efficiency more than 18-fold (from 4.7 to 87.3 M⁻¹ s⁻¹) through the introduction of a stabilizing 24-residue helix-turn-helix motif.^[44] This enhancement, validated by X-ray crystallography aligning with player models, improved the enzyme's ability to catalyze a key [4+2] cycloaddition reaction, demonstrating Foldit's utility in optimizing biocatalysts for industrial processes like sustainable chemical synthesis and biofuel production.^[44]

Recent Contributions (2020–2025)

In 2020, amid the COVID-19 pandemic, Foldit players participated in puzzles aimed at designing protein binders for the SARS-CoV-2 spike protein, producing thousands of candidate structures that informed antiviral drug development efforts.^[4] In 2023, the Foldit community launched the Drugit initiative, a crowdsourcing effort where players utilized the game's interface to design non-peptidic small-molecule binders targeting the von Hippel-Lindau (VHL) protein, a key regulator in cellular degradation pathways.^[41] This project leveraged human intuition to explore chemical space beyond traditional computational methods, resulting in novel binder designs that demonstrated binding affinities in the micromolar range.^[41] The outcomes were published in Nature Communications in April 2025, highlighting the potential of gamified crowdsourcing for advancing targeted protein degradation therapies.^[41] From 2024 to 2025, Foldit players contributed to refining protein structure models in global databases through dedicated puzzle series integrated with experimental data. A study led by researchers at the University of Massachusetts Dartmouth, published in October 2025, analyzed player-submitted solutions against original models in the Protein Data Bank, finding that top Foldit designs improved atomic accuracy by up to 20% in many cases, outperforming initial depositions without human intervention.^[45] These refinements enhanced the reliability of public protein repositories, aiding downstream applications in structural biology and drug discovery. The 2024 Nobel Prize in Chemistry, awarded to David Baker for computational protein design, underscored the foundational impact of Rosetta software—the engine powering Foldit—on the field.^[6] Baker's work, which enabled the de novo creation of novel proteins, indirectly elevated Foldit's role in democratizing such designs through citizen science, fostering renewed interest in hybrid human-AI approaches to protein engineering.^[46]^[6]

Community and Impact

Player Engagement

Foldit has amassed over 750,000 players as of 2020, creating a vibrant global community that drives ongoing contributions to protein folding research.^[47] This player base encompasses a diverse mix of gamers, scientists, and students, with survey data revealing varied educational backgrounds—from high school to advanced degrees—and professional experiences that span multiple fields.^[38] The absence of a typical demographic profile allows for broad participation, including international teams formed through dedicated forums and group features, where players collaborate across time zones to tackle complex puzzles.^[14] Key social tools foster interaction and knowledge exchange within the community. In-game chat, powered by IRC technology, enables real-time discussions among players, while the recipe-sharing system allows users to create, upload, and rate custom scripts—automated macros that execute folding maneuvers—enhancing collective problem-solving.^[48]^[49] Competitive elements, such as tournaments and periodic challenges aligned with events like the Critical Assessment of Structure Prediction (CASP), encourage rivalry and cooperation, with top-ranked players often serving as pivotal contributors who refine and optimize solutions for the most difficult puzzles.^[8]^[34] To maintain long-term involvement, Foldit employs retention strategies centered on regular content updates and community reinforcement. Weekly puzzle releases provide fresh challenges, keeping players engaged with evolving scientific goals, while special events like developer chats and collaborative competitions build excitement.^[50]^[51] Researchers offer direct feedback on player submissions, acknowledging high-impact solutions in publications and underscoring their role in advancing biochemistry, which motivates sustained participation.^[14] Efforts to promote diversity in citizen science are evident in Foldit's design, which lowers barriers for underrepresented groups by emphasizing intuitive gameplay over formal expertise, thereby attracting a wide array of participants from varied socioeconomic and cultural backgrounds.^[52] This inclusive approach, supported by multilingual accessibility and global outreach, helps broaden involvement in scientific discovery beyond traditional demographics.^[53]

Educational and Broader Reach

Foldit has been integrated into educational settings since its early development, with Foldit Standalone introduced in 2017 to enable offline protein manipulation suitable for classroom environments without internet access.^[54] This version allowed educators to facilitate hands-on learning in biochemistry by providing tools for direct structure editing and scoring, bypassing the need for the full online platform.^[55] In 2020, Foldit Education Mode was introduced as a dedicated self-guided tutorial series, designed specifically for classroom use to teach core concepts in protein biochemistry through interactive puzzles.^[28] This mode progresses students from basic amino acid properties to advanced folding mechanics, supporting integration into high school biology curricula and university-level bioinformatics courses.^[56] Educators have leveraged its custom contest feature to tailor puzzles to specific lesson plans, enhancing engagement in molecular biology topics.^[57] The 2025 release of Education Mode v2 marks a significant advancement, transitioning to a fully web-based format that eliminates download requirements and features an improved user interface with expanded puzzles for deeper learning.^[29] These updates lower technical barriers, enabling broader global accessibility for students in resource-limited settings and facilitating seamless use in remote or hybrid classrooms.^[29] Foldit's educational outreach extends through partnerships with organizations like SciStarter, which hosts the game as a citizen science project to connect learners with real-world biology applications across middle school to graduate levels.^[58] Similarly, collaboration with PBS has amplified its visibility, including a 2016 NOVA scienceNOW segment that highlighted Foldit's role in democratizing scientific discovery.^[59] Beyond formal education, Foldit inspires broader citizen science initiatives by engaging diverse participants worldwide, fostering interest in STEM fields and promoting inclusivity through its intuitive design that welcomes non-experts.^[45] This global player base, spanning varied backgrounds, contributes to a more diverse STEM community by demonstrating how gaming can bridge gaps in scientific participation.^[60]

Future Directions

Ongoing Enhancements

In 2025, Foldit introduced Education Mode v2 as a fully web-based platform, accessible at play.fold.it without requiring downloads, thereby enhancing user accessibility across various devices including mobile browsers.^[29] This rollout features an updated user interface with streamlined navigation and an expanded set of introductory puzzles designed to progressively build players' understanding of protein structures, allowing for more intuitive handling of complex folding challenges.^[29] The enhancements aim to lower barriers to entry while maintaining the game's core mechanics, as supported by a recent quantitative evaluation demonstrating improved learning outcomes in biochemistry concepts through gameplay.^[61] Ongoing development incorporates player input through direct feedback channels, such as email submissions to the Foldit team, which inform iterative refinements to puzzle design and interface usability.^[29] For instance, community suggestions have contributed to better cross-device compatibility, enabling smoother experiences on tablets and smartphones via the web version. This feedback-driven approach ensures updates align with diverse player needs, fostering sustained engagement without overhauling established features. A November 2025 publication highlighted Foldit players' contributions to refining protein structures in the PDB-REDO database, demonstrating ongoing integration with structural biology resources through new puzzle series.^[62] To support long-term viability, Foldit recruited a dedicated developer in 2024, with funding extending through fiscal year 2025, focused on bolstering cyber infrastructure for efficient distributed computing operations.^[63] These optimizations target server scalability and resource management, allowing the platform to handle increased player traffic and computational demands from collaborative protein modeling efforts. By prioritizing backend stability, the team ensures reliable puzzle processing and data sharing, essential for the game's role in crowdsourced research.

Expansion Opportunities

The Drugit interface enables players to engage in ligand design for small-molecule drug discovery by building and refining non-peptidic binders, such as those targeting the von Hippel-Lindau protein.^[41] This feature, demonstrated in puzzles where over 300 players generated thousands of molecular designs, was outlined in a 2025 publication on its use within the Foldit platform.^[64] Additionally, there is potential for introducing RNA folding puzzles, as custom Foldit contests have already supported RNA structure modeling alongside proteins and ligands in educational and research contexts.^[57] Beyond traditional protein folding, Foldit holds interdisciplinary potential in materials science, where player-designed de novo proteins could enable the creation of self-assembling protein-based nanomaterials for applications like drug delivery or sensors.^[65] In environmental biotechnology, the platform has facilitated enzyme redesigns to degrade toxins, such as aflatoxins in agriculture, highlighting its adaptability to bioremediation challenges.^[66] Key challenges for expansion include scaling simulations to accommodate a million players, given the existing base of over 240,000 registered players, which would require enhanced computational infrastructure to handle distributed modeling without performance degradation.^[67] Ethical considerations in crowdsourced drug design, such as ensuring equitable credit for anonymous contributors and mitigating risks of unintended molecular designs, must also be addressed through institutional review board oversight.^[68]^[69] Long-term goals emphasize deeper human collaboration via video games, as explored in 2025 publications on video game-assisted molecular reconstruction, to accelerate discoveries in structural biology.^[70]

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Foldit Standalone is designed to allow easy, real-time, direct manipulation of protein structures, while also giving access to the extensive power of Rosetta ...Missing: redesign | Show results with:redesign
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Algorithm discovery by protein folding game players - PNAS
Foldit is a multiplayer online game in which players collaborate and compete to create accurate protein structure models. For specific hard problems, ...Missing: rotating freezing
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Introducing Foldit Education Mode | Nature Structural & Molecular ...
Aug 17, 2020 · We have recently introduced Custom Contests, a feature that allows educators to create, administer and grade their own Foldit puzzles to fit ...
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Foldit Standalone: a video game-derived protein structure ... - NIH
Funding. This work was supported by the National Science Foundation [1629879]; the National Institutes of Health [1UH2CA203780]; and RosettaCommons. Conflict of ...
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Foldit uses Rosetta to calculate free energy. Specifically, there's a Rosetta Energy Function, which does scoring. Foldit currently uses the REF2015 version of ...
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Foldit rankings | Foldit Wiki - Fandom
Foldit ranks players by "global points" on completed puzzles, with separate rankings for soloists, evolvers, and groups, based on 120-day, weekly, monthly, and ...Missing: achievements | Show results with:achievements
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Foldit user interface/Undo menu - Foldit Wiki - Fandom
Hovering over a point in the undo graph show the score at that point. Clicking on that point restores the protein to that score.Missing: real- time
[35]
De novo protein design by citizen scientists - PMC - NIH
Foldit players in one case redesigned a loop region of an already folded structure, but the de novo design of an entire protein is a far more expansive ...
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AlphaFold - Foldit Wiki - Fandom
AlphaFold is an algorithm for predicting the 3D structure of proteins based on their primary structure, the sequence of amino acids that make up the protein.
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Aug 1, 2021 · Amazing new AI software is now at your fingertips, and you can use it to boost confidence in your own protein designs!
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[PDF] De novo protein design by citizen scientists - Baker Lab
Citizen scientists used the Foldit game to design proteins by crafting folded structures from a peptide chain, exploring new regions, unlike Rosetta.
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Foldit Notches a Protein Structure Success (And Some Failures)
Sep 20, 2011 · The Foldit collaboration participated in the latest iteration of a regular protein-structure prediction challenge, CASP9. And their results varied.Missing: process | Show results with:process
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An analysis and evaluation of the WeFold collaborative for protein ...
Jul 2, 2018 · That is, the starting points provided to Foldit players by a MESHI selection among server models were overall better than those selected by ...
[41]
6MSP: De novo Designed Protein Foldit3 - RCSB PDB
Jun 12, 2019 · One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were ...
[42]
Crystal structure of a monomeric retroviral protease solved ... - Nature
Sep 18, 2011 · In proof-of-concept tests, Foldit players—most of whom have little or no background in biochemistry—were able to solve protein structure ...
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De novo protein design by citizen scientists - Nature
Jun 5, 2019 · De novo protein design by citizen scientists. Nature 570, 390–394 (2019). https://doi.org/10.1038/s41586-019-1274-4. Download citation.
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Drugit: crowd-sourcing molecular design of non-peptidic VHL binders
Apr 14, 2025 · The Foldit interface is tailored to empower players with limited prior knowledge to solve molecular design problems, and through it, members of ...
[45]
UMass Dartmouth researcher advances global protein databases ...
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UW's David Baker wins Nobel Prize for solving protein puzzles
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Real Progress In Crowdsourcing Scientific Tasks To Gamers
Nov 4, 2020 · Cooper is co-creator of Foldit, where the competition is about protein folding and design. ... million players, Cooper continues. It has ...
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IRC Chat - Foldit Wiki - Fandom
Foldit's in-game chat is based on IRC ("Internet Relay Chat"). Anyone may connect to the Foldit IRC server either through the Foldit game client or an external ...
[50]
Algorithm discovery by protein folding game players - PMC - NIH
Foldit is a multiplayer online game in which players collaborate and compete to create accurate protein structure models. For specific hard problems, Foldit ...Missing: modes | Show results with:modes<|separator|>
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101 - Puzzle Levels and Types - Foldit Wiki
Foldit offers two levels of puzzles that are played for points. New players who have completed intro puzzles can play beginner puzzles, and all players can play ...Missing: fundamentals progression
[52]
101 - Feedback and Collaboration - Foldit Wiki
Groups are an integral part of Foldit and have their own chat rooms and forums. Chat events. Foldit runs occasional science and developer chats, where Foldit ...
[53]
Online citizen science games: Opportunities for the biological ... - NIH
The rationale for the development of Foldit was to harness the collective problem-solving abilities of non-experts and to exploit a wide diversity of playing ...
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Behind the Scenes of Foldit, Pioneering Science Gamification
Nov 20, 2012 · Foldit is a popular online citizen-science game, in which players are scored on the structure of proteins that they've folded. In Foldit puzzles ...<|control11|><|separator|>
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Foldit Standalone: a video game-derived protein structure ... - PubMed
Sep 1, 2017 · Foldit Standalone is designed to allow easy, real-time, direct manipulation of protein structures, while also giving access to the extensive power of Rosetta ...Missing: precursor | Show results with:precursor
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Foldit standalone - Foldit Wiki - Fandom
The standalone version of Foldit includes most of the features and functions found in the game version of Foldit, along with a few more specialized tools.Missing: 2012 | Show results with:2012<|separator|>
[57]
(PDF) Introducing Foldit Education Mode - ResearchGate
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Creating Custom Foldit Puzzles for Teaching Biochemistry - PMC - NIH
Foldit Standalone is version of the Foldit game that gives the puzzle designer control over setting up their puzzle, which aids in puzzle design and testing.Missing: progression | Show results with:progression
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Foldit - SciStarter
Mar 18, 2022 · Players compete with one another to discover high-scoring protein folds, which represent a protein's physical structure. Knowing the structure ...Missing: fundamentals core actions collaborative modes
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http://modlab.ucdavis.edu/digitalprojects/foldit-first-contact/
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Foldit: First Contact - ModLab - UC Davis
As an online video game about protein folding, Foldit enables citizen scientists around the world to contribute meaningfully to computational biochemistry ...
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Welcome Andreas Petrides: The New Foldit Developer at OMSF
Jul 1, 2024 · Andreas's position is supported through the 2025 fiscal year with the goal of positioning Foldit to be more competitive for cyber infrastructure ...
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Foldit players tackle real-world drug design - YouTube
Apr 25, 2025 · Foldit's Small Molecule Drug Design just scored a peer-reviewed victory! 333 players designed more than 6.5 k molecules in 10 puzzles; ...
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Protein design by citizen scientists - Baker Lab
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Scientists' Newest Tool To Fight Agricultural Toxin: A Video Game
Feb 28, 2018 · Developers of Foldit's "Aflatoxin Challenge" believe this huge protein, called an enzyme, can destroy aflatoxin - but only if it's reconfigured ...
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Aug 9, 2025 · In this paper, we will demonstrate that the crowdsourcing model of research has the potential to cause harm to participants, manipulates the ...
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A wide range of quality and ethical issues relate to crowdsourced R&D. Growing points. The rapid growth in applications of crowdsourced R&D in medical ...
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Foldit publications - Foldit Wiki - Fandom
An article published in Nature Scientific Reports in 2018 describing Foldit's role in the WeFold collaboration in CASP 10 and 11. The contribution of Foldit ...Missing: loops | Show results with:loops