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Rosetta@home

Rosetta@home is a volunteer distributed computing project that utilizes the BOINC platform to aggregate the idle computational resources of personal computers worldwide, enabling the Rosetta software to predict and design three-dimensional protein structures and complexes.^[1] Launched on June 26, 2005, by the Baker Laboratory at the University of Washington, it addresses the computationally intensive challenge of protein folding—a core problem in biology that underpins disease mechanisms and therapeutic development.^[2] By crowdsourcing calculations, the project has democratized access to supercomputer-level processing power, allowing researchers to simulate protein conformations that would otherwise require years of dedicated hardware.^[1] The initiative focuses on advancing understanding of how proteins fold into functional shapes and interact, with applications in modeling disease-related proteins such as those involved in HIV, malaria, cancer, and Alzheimer's disease.^[1] Volunteers install the BOINC client software, which downloads small tasks (work units) for the Rosetta algorithm to optimize protein models through energy minimization and conformational sampling.^[1] This approach not only accelerates structure prediction but also supports de novo protein design, where novel sequences are created from scratch to perform specific functions, potentially reducing reliance on costly experimental techniques like X-ray crystallography.^[3] Rosetta@home's contributions have been pivotal in broader scientific breakthroughs, including half of the 2024 Nobel Prize in Chemistry awarded to David Baker, Demis Hassabis, and John Jumper for computational protein design and protein structure prediction, which built on the Rosetta framework's innovations in structure prediction and novel protein creation.^[3] The project has powered numerous studies, from virtual screening for drug candidates to peptide simulations, and integrates with related efforts like the citizen science game Foldit, which gamifies protein modeling to engage non-experts.^[4] As a non-profit endeavor supported by the Rosetta Commons—a collaborative consortium of over 50 laboratories and institutions worldwide—it continues to evolve, incorporating AI enhancements to refine predictions and expand its impact on biomedical research.^[5]^[6]

History and Development

Founding and Launch

Rosetta@home was founded in 2005 by the laboratory of David Baker at the University of Washington, emerging as a pioneering volunteer computing project built on the BOINC infrastructure to facilitate distributed protein modeling. The initiative was spearheaded by Baker, a biochemist specializing in computational protein design, who served as the principal investigator, with key contributions from collaborators within the Rosetta Commons, a multi-institutional consortium dedicated to advancing Rosetta software for macromolecular modeling. This effort transformed the academic Rosetta tool, originally developed for protein structure prediction, into a scalable distributed system capable of leveraging global volunteer resources.^[7] The project's initial goals centered on harnessing the idle processing power of personal computers worldwide to address computationally intensive challenges in protein structure prediction—problems that even the most powerful supercomputers of the era could not solve efficiently due to the vast conformational search spaces involved. By distributing Rosetta's algorithms across volunteer machines, Rosetta@home aimed to generate large ensembles of protein models, improving predictions for de novo folding and refinement tasks that underpin biomedical research. This approach democratized access to high-performance computing, enabling breakthroughs in understanding protein folding pathways without reliance on centralized resources.^[1]^[8] Rosetta@home officially launched in the summer of 2005, with the first work units released on June 29, marking the distribution of initial ab initio folding tasks to Windows and Linux volunteers, which quickly produced thousands of protein structures. Early operations were supported through partnerships with the BOINC platform, developed by researchers at the University of California, Berkeley, providing the robust framework for task allocation, validation, and result aggregation essential to the project's success. By late 2005, the platform had expanded to include Mac OS X support, setting the stage for rapid growth in participant engagement.^[2]

Key Milestones and Evolution

In 2008, Rosetta@home achieved its first major successes in protein design, with computational models leading to experimentally validated novel enzymes, such as a catalyst for the retro-aldol reaction that demonstrated activity in laboratory tests. This milestone highlighted the project's capacity for de novo protein creation, leveraging distributed computing to explore vast conformational spaces beyond traditional lab capabilities.^[9] By 2011, the project's efforts were complemented by Foldit, a gamified platform that enabled citizen scientists to interactively refine protein structures, resulting in breakthroughs like the accurate modeling of a retroviral protease that had eluded experts for over a decade. This collaboration expanded participation, blending volunteer computing with human intuition to accelerate structure prediction and design tasks.^[10] During the 2020-2022 COVID-19 pandemic, Rosetta@home played a pivotal role in vaccine development, contributing computational designs to the SKYCovione nanoparticle vaccine, which received full approval in South Korea in June 2022 after demonstrating a superior neutralizing antibody response to the Oxford/AstraZeneca vaccine in clinical trials.^[11] The project's distributed resources facilitated rapid screening of protein variants, aiding the creation of stable, non-refrigerated vaccine candidates.^[12] From 2024 to 2025, Rosetta@home shifted strategic focus toward small molecule and peptide design, incorporating large-scale virtual screening protocols like RosettaVS to support drug discovery where AI models face limitations in ligand interactions.^[13] This evolution was marked by the release of Foldit Education Mode v2 in August 2025, a web-based update enhancing accessibility for biochemistry education without requiring downloads.^[14] By November 2025, the project had grown to over 1.3 million registered users and 4.5 million hosts, reflecting sustained volunteer engagement amid these advancements.^[15] Under the management of the Baker Lab at the University of Washington, following expansions of the Institute for Protein Design, Rosetta@home continues to integrate BOINC infrastructure for scalable biomolecular simulations.^[16]

Computing Platform

BOINC Infrastructure

Rosetta@home utilizes the Berkeley Open Infrastructure for Network Computing (BOINC), an open-source middleware platform designed to manage volunteer computing resources across distributed networks of personal computers. BOINC facilitates the allocation of idle CPU time from volunteers worldwide, enabling the execution of computationally intensive tasks without requiring dedicated hardware infrastructure. This framework supports seamless integration for scientific projects by handling resource discovery, task scheduling, and result aggregation in a decentralized manner.^[17] The project's server architecture is hosted and maintained by the Baker Laboratory at the University of Washington, which oversees core operations including job submission via a centralized scheduler, result validation through automated assimilators, and credit allocation to participants based on verified contributions. The scheduler distributes computational work units to volunteer clients, while validators compare outputs from multiple independent computations to ensure accuracy and reliability. This setup allows the Baker Lab to scale operations efficiently, processing approximately 4,400 successful jobs daily as of November 2025, while generating approximately 1.38 million credits for volunteers in the same period.^[18]^[19] To safeguard volunteer machines, BOINC implements sandboxed execution environments that isolate Rosetta@home applications, preventing unauthorized access to system resources or files; on platforms like macOS, this includes restricted permissions for the BOINC directory. Additionally, cross-validation mechanisms require identical results from at least two or more volunteer hosts before granting credits, mitigating errors from hardware faults or malicious activity. These features collectively ensure secure and trustworthy distributed computing.^[20]^[17] Rosetta@home applications primarily run on CPUs and are compatible with a wide range of operating systems, including Windows, macOS, and Linux distributions, as well as ARM-based architectures like Android and 64-bit Linux. No GPU acceleration is currently supported for standard tasks, emphasizing broad accessibility over specialized hardware. The Rosetta software serves as the core computational payload within this BOINC framework, performing protein structure predictions and designs.^[21]

Task Distribution and Processing

Scientists submit protein models and design challenges through a web interface provided by the Baker Laboratory, where the central server processes these inputs into smaller computational subtasks, such as Monte Carlo simulations for protein folding pathways.^[1]^[22] These subtasks are formatted as workunits, each representing a discrete segment of the overall simulation, enabling parallel processing across the distributed network.^[23] Workunits are distributed to volunteer clients via the BOINC platform, which matches tasks to participating computers based on reported hardware capabilities, user preferences, and estimated completion times to optimize efficiency.^[18] Typical task runtimes range from 1 to 24 hours, with recent averages around 7.2 hours for standard applications, allowing volunteers to contribute during idle periods without significant disruption.^[15] Validation employs a quorum system, with minimum quorum typically 1 but varying by task to ensure consensus through replication if needed; if initial results diverge, an additional task is issued to resolve discrepancies and ensure accuracy.^[24] Failed or erroneous tasks trigger automatic resubmission to other clients until the quorum is met or a deadline expires, minimizing data loss and maintaining result reliability. Upon successful validation, BOINC awards credits to volunteers proportional to the computational effort of completed tasks, fostering participation; for instance, approximately 1.38 million credits were granted across the network in the last 24 hours as of November 2025.^[15] The system's scalability leverages a global volunteer base exceeding 1.3 million users and 4.5 million hosts, delivering 13.8 teraFLOPS of sustained performance and enabling petascale-level computations for complex protein modeling that surpass individual supercomputer capacities.^[18]^[23]

Scientific Goals and Significance

Protein Structure Prediction

Proteins must fold into precise three-dimensional (3D) structures to carry out their biological functions, yet predicting these structures from amino acid sequences alone remains a central challenge in biology due to the enormous number of possible conformations and the subtle balance of physical forces involved. Rosetta@home tackles this protein folding problem by distributing computational tasks that employ the Rosetta software's energy minimization algorithms to sample and evaluate vast numbers of potential conformations, identifying those with the lowest free energy as likely native states. This approach draws on principles of statistical thermodynamics to model the folding landscape, where proteins are assumed to adopt the global energy minimum under physiological conditions. The core method for de novo structure prediction in Rosetta@home is fragment assembly, which builds candidate models by stitching together short polypeptide fragments (typically 3 or 9 residues long) derived from experimentally determined structures in the Protein Data Bank, selected via sequence and secondary structure similarity. Sampling proceeds through Monte Carlo optimization, where fragments are inserted and adjusted to minimize an energy score, progressing in stages: first, a coarse-grained centroid mode represents residues as single points to rapidly explore backbone topologies and avoid local traps; second, an all-atom refinement stage repacks side chains and relaxes the full structure using a detailed force field that accounts for bond lengths, angles, van der Waals clashes, hydrogen bonds, and implicit solvation effects. This staged protocol efficiently navigates the rugged energy landscape, generating diverse low-energy decoys that approximate the native fold.^[25] Protein structure prediction via Rosetta@home holds significant value by complementing experimental techniques such as X-ray crystallography, which, despite offering atomic-level resolution, is constrained by the difficulty of obtaining suitable protein crystals—often successful for only a minority of targets—and its inability to capture dynamic or transient states, often requiring extensive optimization that delays results by months or years. The project has played a pivotal role in the Critical Assessment of Structure Prediction (CASP) competitions, where Rosetta-based methods, powered by volunteer computing, have produced models with root-mean-square deviation (RMSD) values under 5 Å for small proteins (<150 residues), rivaling experimental accuracies and highlighting the protocol's reliability for challenging targets without templates.^[26]^[27] A major strength of Rosetta@home lies in its distributed computing model, which mobilizes the processing power of tens of thousands of active volunteer computers to perform exhaustive conformational sampling—producing up to 10^6 decoys per protein target, orders of magnitude beyond single-machine capabilities—thus enhancing the chances of capturing near-native structures through sheer statistical coverage of the folding pathways. The resulting outputs are ensembles of decoy models, scored and ranked by Rosetta's energy function; these are clustered by Cα-atom RMSD to identify consensus folds, with top-ranked decoys archived in prediction databases for benchmarking against NMR or cryo-EM data and serving as starting points for broader applications like protein design.^[27]^[28]

Protein Design and Applications

Rosetta@home facilitates de novo protein design by leveraging the distributed computing power of volunteers to enumerate and optimize amino acid sequences that stably fold into predefined target structures, utilizing Rosetta's physics-based scoring functions to evaluate energetic favorability. This approach begins with generating novel protein backbones through fragment assembly or ideal helix/strand placement, followed by sequence optimization to minimize the energy gap between the target fold and alternative conformations. Volunteer-hosted computations play a critical role in sampling vast conformational spaces to refine these designs, ensuring predicted structures are thermodynamically stable without relying on natural templates.^[2] The design process involves iterative cycles of backbone generation, side-chain packing, and energy minimization, where Rosetta@home tasks perform Monte Carlo simulations to test sequence variants for folding accuracy and stability. For instance, side-chain rotamer libraries are sampled to pack hydrophobic cores while optimizing polar interactions on the surface, with volunteer results feeding back into centralized servers for further refinement.^[29] This distributed validation step is essential for scaling designs that would otherwise be computationally prohibitive on single machines.^[13] Applications of these designs span enzyme engineering for sustainable technologies, including biofuels production through custom catalysts that enhance metabolic pathways for carbon fixation.^[30] In nanomaterials, Rosetta@home supports the creation of self-assembling protein scaffolds with precise geometries for applications like drug delivery vehicles. For therapeutics, the platform enables the development of novel binding proteins with high specificity, such as de novo scaffolds that modulate cellular processes. Seminal work includes the 2003 design of Top7, a 93-residue protein with a novel fold achieved through Rosetta's early protocols, which served as a foundational precursor for subsequent therapeutic advancements. By 2025, evolutions of this methodology have yielded designed proteins advancing to clinical candidates, demonstrating the platform's impact on translating computational designs into functional biomolecules. Looking ahead, Rosetta@home's 2025 shifts toward large-scale screening of drug-like peptides and virtual simulations underscore its growing role in accelerating therapeutic discovery pipelines.^[13]

Research Applications

Rosetta@home has advanced disease research by providing distributed computing power to support Rosetta software in modeling protein structures implicated in various pathologies, aiding the design of potential therapeutics through predictions of folding, docking, and interactions.^[31] These efforts focus on simulating complex biomolecular assemblies that are challenging to resolve experimentally, providing structural insights that guide inhibitor and vaccine development. In Alzheimer's disease research, Rosetta simulations have modeled amyloid-beta aggregates, facilitating the design of cyclic peptides that stabilize non-toxic conformations and inhibit oligomer formation, a key step in plaque buildup.^[32] Similarly, ensemble-based modeling has targeted tau protein tangles, designing variants that resist aggregation while preserving microtubule binding, as validated through NMR and cellular assays.^[33] These structures inform inhibitor designs aimed at disrupting pathological filaments without affecting normal tau function. For anthrax, Rosetta modeling contributed to predicting the docking of lethal factor to protective antigen in the toxin complex, generating low-energy models that aligned closely with subsequent crystal structures and supported vaccine target identification.^[34] This work highlighted the platform's utility in simulating toxin-receptor interactions for biodefense applications. Studies on herpes simplex virus 1 (HSV-1) utilized Rosetta for docking viral glycoproteins, such as gD, to host cell receptors, revealing binding interfaces that aid in developing entry inhibitors.^[35] RosettaDock protocols predicted antibody-surface protein complexes with atomic accuracy, informing therapeutic antibody engineering.^[35] In HIV research, Rosetta has supported the design of broadly neutralizing antibodies by mapping epitopes on the envelope glycoprotein, enabling the creation of immunogens that activate rare precursor B cells for vaccine strategies.^[36] Computational epitope-focused designs have improved antibody potency against diverse strains, as demonstrated in immunization studies.^[37] For malaria, caused by Plasmodium falciparum, Rosetta predicted structures of circumsporozoite protein repeats, optimizing nanoparticle immunogens that enhance antibody responses and transmission-blocking potential.^[38] Additional modeling of invasion complexes, like PfRCR, used Rosetta to stabilize variants for structural validation, identifying druggable sites on parasite proteins.^[39] During the COVID-19 pandemic, Rosetta@home accelerated modeling of the SARS-CoV-2 spike protein, contributing to de novo designs of receptor-binding domain nanoparticles that elicited robust neutralizing antibodies.^[12] These efforts directly informed SKYCovione, a computationally designed vaccine approved in South Korea in 2023, demonstrating high efficacy against variants.^[40] In cancer research, Rosetta@home has enabled the engineering of therapeutic proteins, such as designing high-affinity binders to immune modulating receptors like PD-L1 and CTLA-4 for cancer immunotherapy.^[41] De novo proteins with anti-cancer activity, including bispecific inhibitors, were validated in cellular models, showcasing the platform's role in precision oncology.^[2] Overall, Rosetta@home's distributed simulations have contributed to numerous peer-reviewed publications, many validating computational predictions through experiments and advancing therapeutic pipelines for these diseases.^[18]

Broader Biomedical and Materials Research

Rosetta@home has contributed to clean energy research by enabling the computational design of enzymes that enhance biofuel production, such as optimizing cellulases to more efficiently break down plant biomass into fermentable sugars.^[18]^[42] These efforts leverage distributed computing to explore vast conformational spaces, identifying variants with improved thermal stability and catalytic efficiency for industrial applications.^[43] In materials science, the project supports the creation of self-assembling protein nanostructures, which form ordered architectures like filaments and cages suitable for applications in sensors and targeted drug delivery systems.^[18]^[44] These designs rely on principles of protein design to specify symmetric interfaces that drive precise assembly at the nanoscale, enabling tunable properties for non-biological uses.^[45] For drug discovery beyond traditional targets, Rosetta@home facilitates virtual screening of small molecules against diverse protein targets, with expansions as of 2024 enabling the evaluation of large compound libraries through the RosettaVS protocol.^[18]^[46] This physics-based approach prioritizes binding affinity and specificity, accelerating the identification of leads for pharmaceutical development.^[47] The platform also advances peptide simulations, modeling flexible and cyclic peptides to develop antimicrobial agents with enhanced stability and potency.^[18]^[48] These simulations explore non-canonical amino acid compositions to optimize sequences for broad-spectrum activity against pathogens.^[49] Collaborations with the Rosetta Commons consortium integrate Rosetta@home's computing power into interdisciplinary projects, fostering shared advancements in biomolecular modeling across academic and industrial labs.^[50]^[18] Recent expansions incorporate AI-driven hybrid modeling, combining tools like RosettaFold with traditional physics-based simulations to design novel biomolecular structures for non-traditional applications in energy and materials.^[18]^[51]

Rosetta Software Suite

Core Protocols and Tools

The core protocols and tools in the Rosetta software suite, which power the distributed computing efforts of Rosetta@home, focus on physics-based modeling of protein structures and interactions using full-atom representations. These protocols enable volunteer-contributed computations to explore conformational spaces, optimize sequences, and predict complexes, contributing to advancements in protein structure prediction and design. Central to these tools is a scoring function that evaluates model quality by approximating physical interactions, allowing for iterative refinement through sampling and minimization techniques. RosettaDesign is a key protocol for optimizing amino acid sequences to stabilize given protein backbones, employing Monte Carlo sampling to explore sequence space while minimizing the energy of side-chain packing and backbone interactions. This method generates low-energy sequences by iteratively proposing amino acid substitutions and rotamer adjustments, accepting or rejecting changes based on the change in total energy, which facilitates the design of proteins with desired folds or functions. In Rosetta@home, RosettaDesign tasks distribute these computations across volunteer machines to generate diverse sequence variants for subsequent analysis.^[52] RosettaDock addresses protein-protein and protein-ligand interactions through a multi-stage docking algorithm that combines rigid-body transformations with flexible side-chain and backbone refinements. It begins with low-resolution centroid-mode sampling to identify initial binding orientations, followed by high-resolution all-atom refinement using Monte Carlo minimization to optimize interface residues and resolve steric clashes. This protocol has been integral to Rosetta@home's prediction of protein complexes, where distributed tasks perform extensive sampling of docking poses to identify near-native configurations.^[52] The Robetta server provides an automated pipeline for full-atom protein modeling, integrating comparative modeling, ab initio prediction, and domain assembly using Rosetta's fragment-insertion techniques. It processes input sequences by generating fragment libraries, assembling models via iterative backbone building and side-chain packing, and clustering results to select high-confidence predictions. In the context of Rosetta@home, Robetta-like automation supports the scaling of these pipelines across distributed resources for large-scale structure prediction challenges.^[52] Additional tools include RosettaScripts, which allows users to define custom protocols by combining movers, filters, and tasks in an XML-based scripting language for flexible workflow orchestration, and the Relax protocol, which performs all-atom energy minimization through cycles of torsion-angle gradient descent and side-chain repacking to resolve local strain in models. These extend the suite's versatility for specialized applications in Rosetta@home.^[52] At the foundation of these protocols lies the Rosetta full-atom energy function, which scores conformations as E = \sum of interaction potentials, including van der Waals repulsion and attraction, hydrogen bonding, solvation effects, and electrostatics, derived from empirical parameters fitted to experimental data. This additive form enables efficient evaluation during sampling, guiding optimizations toward physically realistic structures.^[52] Validation of these core tools has shown robust performance, with RosettaDesign and related protocols achieving experimental success in de novo protein designs, where designed sequences folded into intended structures as confirmed by crystallography and spectroscopy.

Interactive and AI-Enhanced Components

Foldit serves as a prominent interactive component of the Rosetta@home project, offering a gamified interface that enables users to manually manipulate and fold virtual proteins using intuitive controls and puzzle-based challenges. Developed by the University of Washington's Center for Game Science in collaboration with the Baker laboratory, Foldit was publicly released in beta form in May 2008, transforming the computational protein folding process into an engaging multiplayer game. Players leverage human spatial reasoning to optimize protein structures, often outperforming automated algorithms in specific scenarios, such as symmetric fold explorations or complex puzzle solutions. This crowdsourced approach allows volunteers to directly contribute to scientific research by generating viable protein models that inform Rosetta@home's distributed computing efforts.^[53] A key evolution in Foldit's interactivity is its Education Mode, which facilitates learning through guided tutorials on protein biochemistry and folding mechanics. Initially launched in August 2020 to support remote teaching during the COVID-19 pandemic, the mode was updated to version 2 in August 2025, introducing a fully web-based platform accessible without software downloads. This version enhances user experience with streamlined interfaces, immediate puzzle loading, and integrated feedback mechanisms, enabling educators and students to explore concepts like secondary structure formation and energy minimization in real-time. By integrating Foldit solutions into Rosetta@home workflows, volunteers' puzzle-solving outputs seed refinement tasks on distributed networks, accelerating the validation of novel protein designs for biomedical applications.^[14]^[54] Complementing these interactive elements, AI-enhanced components like RoseTTAFold represent a deep learning advancement within the Rosetta ecosystem, introduced in 2021 to provide rapid, accurate protein structure predictions. RoseTTAFold employs a three-track neural network that processes one-dimensional sequence data, two-dimensional distance maps, and three-dimensional coordinates, enabling de novo folding predictions in minutes on standard hardware. Integrated into the Rosetta software suite used by Rosetta@home, it generates initial structural models that volunteers' computational resources subsequently refine through sampling and optimization protocols. This hybrid approach accelerates distributed task processing by prioritizing promising conformations, reducing the search space for complex simulations. A 2024 extension, RoseTTAFold All-Atom, further advances the suite by modeling ligands and covalent modifications.^[55]^[56]^[57] The impacts of these components are evident in tangible research outcomes. For instance, Foldit players collaboratively designed 56 novel, stable proteins from scratch, including one with a unique fold, as validated experimentally and published in 2019; these designs have potential applications in vaccine development and enzyme engineering. Similarly, RoseTTAFold has demonstrated superior performance in protein design tasks compared to AlphaFold, particularly in generating diverse, functional structures for multistate assemblies, as shown in subsequent benchmarks where it achieved higher success rates in hallucinating binder proteins.^[58]^[59]

Comparisons to Similar Projects

Folding@home

Folding@home and Rosetta@home share fundamental similarities as volunteer-driven distributed computing projects that harness idle computational resources from participants worldwide to advance biomolecular research, particularly in protein science. Both leverage the BOINC platform to distribute work units for simulations, enabling large-scale contributions to understanding protein behavior without relying on centralized supercomputing facilities.^[31]^[60] This shared model has democratized access to high-performance computing for biomedical challenges, fostering community involvement in scientific discovery. A key distinction lies in their methodological approaches to protein-related computations. Folding@home specializes in all-atom molecular dynamics simulations, which model the physical movements and interactions of atoms over time to explore protein folding pathways, misfolding events, and dynamic processes relevant to diseases.^[61] In contrast, Rosetta@home employs a hybrid strategy combining coarse-grained representations for initial sampling with full-atom refinement, primarily aimed at predicting native protein structures and enabling de novo design rather than simulating real-time dynamics.^[62]^[1] In terms of scale, Folding@home has demonstrated greater capacity for massive parallelization, especially through extensive GPU utilization; during its 2020 mobilization against COVID-19, it achieved exascale performance exceeding 1.5 exaflops from volunteer contributions, facilitating unprecedented simulations of viral proteins.^[63]^[64] Rosetta@home, while impactful in structure prediction tasks, operates on a comparatively smaller computational footprint, focusing on targeted design challenges.^[65] The projects overlap in their contributions to protein folding research, with both informing seminal studies on structural biology through distributed simulations, though Rosetta@home places stronger emphasis on design-oriented outcomes.^[66] Uniquely, Rosetta@home prioritizes de novo protein creation, generating novel sequences and folds for applications like vaccine development, diverging from Folding@home's core strength in dynamics simulation.^[67]^[61]

World Community Grid and Others

The World Community Grid (WCG), initiated by IBM in 2004, operates as a volunteer computing platform supporting diverse humanitarian research initiatives, such as those targeting cancer, AIDS, clean water access, and climate modeling, through a collection of heterogeneous applications hosted on the BOINC infrastructure.^[68] Unlike Rosetta@home's specialized emphasis on protein structure prediction and de novo design via the Rosetta software suite, WCG encompasses a broader portfolio of projects that integrate various computational tools to address multiple biomedical and environmental challenges.^[18] Notably, certain WCG efforts, including the Human Proteome Folding projects (phases 1 and 2), have employed the Rosetta software to generate structural models of human secreted proteins and those from disease-causing pathogens, thereby complementing but not overlapping with Rosetta@home's ongoing development and application of the tool. Predictor@home, launched in June 2004 as the inaugural BOINC-based project, concentrated on enhancing protein structure prediction accuracy by testing algorithms against sequences in the Critical Assessment of Structure Prediction (CASP) framework, without extending to protein design applications.^[69] This early initiative operated from 2004 until its discontinuation in 2009, underscoring the challenges of sustaining distributed computing efforts in the nascent field of protein modeling.^[66] In comparison, Rosetta@home, launched in 2005, maintains a unified focus on the Rosetta suite for both prediction and design, demonstrating greater longevity and evolution in response to advancing computational biology needs.^[2] Key distinctions among these projects include WCG's support for a diverse array of applications across scientific domains, Rosetta@home's cohesive reliance on a single, iteratively improved software ecosystem, and Predictor@home's narrower emphasis on prediction benchmarking without design-oriented goals.^[70] Rosetta@home benefits from particularly tight integration with experimental laboratory validation, as conducted by the Baker Laboratory at the University of Washington, enabling rapid translation of computational outputs into biophysical confirmations that defunct projects like Predictor@home could not achieve. While volunteers often engage across multiple BOINC projects, including both Rosetta@home and WCG, Rosetta@home's credit system remains distinctly calibrated to metrics of protein modeling performance, such as energy scores and structural accuracy.

Community and Impact

Volunteer Engagement

Volunteers participate in Rosetta@home by downloading the free BOINC client software from the official BOINC website or app stores for various platforms, including Windows, macOS, Linux, Android, and others. After installation, users create an account on the Rosetta@home project page and attach their device to the project, enabling it to download and process computational workunits during idle time. The software operates in the background, supporting both CPU and GPU processing options, and can be configured to limit resource usage to avoid impacting daily activities.^[71]^[72] To incentivize involvement, Rosetta@home employs BOINC's standard credit system, where participants earn points proportional to the computational effort contributed, as measured by floating-point operations performed. These credits fuel individual and team leaderboards, fostering competition and recognition among users. While badges are not a core feature, community discussions have proposed them for milestones like sustained participation or high output, and top contributors often receive acknowledgments in related scientific publications for their role in enabling large-scale simulations.^[73]^[74]^[75] The project maintains an active online community through dedicated forums, where volunteers discuss scientific aspects, share computing experiences in the "Cafe Rosetta" section, and report bugs or technical issues in specialized threads. As of March 2025, Rosetta@home drew from approximately 55,000 active computers contributing worldwide.^[76]^[77] Participation reflects global diversity, with users from over 150 countries, including students and hobbyists, drawn by the project's low barriers—it requires only standard personal hardware without specialized equipment. Some volunteers extend their engagement interactively via the companion Foldit game, which applies Rosetta algorithms in a puzzle format.^[78]^[31] Volunteers face challenges such as managing increased power consumption from prolonged computations, which can raise electricity costs on laptops or desktops running at full capacity. To maintain data integrity, Rosetta@home implements result validation by distributing identical workunits to multiple hosts and comparing outputs; discrepancies lead to invalidation, ensuring only reliable results advance research.^[79]^[80]

Educational and Collaborative Outreach

Rosetta@home's educational initiatives prominently feature the Foldit game, which transforms protein structure prediction into an accessible puzzle-solving experience for learners. Developed by the University of Washington's Baker Lab, Foldit Education Mode was launched in August 2020 as a self-guided tutorial series teaching core concepts in protein biochemistry, such as secondary structure formation and ligand binding, through interactive gameplay.^[81] This mode has been integrated into STEM curricula at high schools and universities, enabling students to explore molecular biology without specialized equipment, fostering hands-on understanding of complex scientific processes.^[14] In August 2025, the release of Foldit Education Mode v2 as a web-based platform further expanded its reach, eliminating the need for software downloads and allowing seamless access in diverse educational settings, including remote and under-resourced classrooms worldwide.^[14] This update builds on the original game's success in engaging non-experts, with educators reporting improved student retention of biochemical principles through gamified challenges that mirror real Rosetta@home simulations.^[81] The project maintains strong collaborations through the Rosetta Commons, a consortium of more than 60 academic institutions^[82] including the University of Washington, Johns Hopkins University, and the University of California, promoting shared development of the Rosetta software suite for protein modeling.^[50] These partnerships facilitate joint research efforts, such as integrating volunteer-generated data into university-led studies on protein design. Additionally, Rosetta@home supports open data sharing by contributing predicted protein structures to the Protein Data Bank (PDB), enabling global researchers to access and validate models derived from distributed computing results.^[82] By harnessing volunteer computing power, Rosetta@home democratizes scientific research, allowing everyday participants to contribute meaningfully to biomedical advancements without formal training.^[83] This approach has accelerated discoveries in protein folding and design, with project outputs cited in over 50 peer-reviewed papers published by the Baker Lab since 2020 alone, spanning topics from enzyme engineering to therapeutic protein development.^[84] Beyond direct outputs, Rosetta@home has inspired a wave of citizen science initiatives, including gamified platforms like Foldit that blend computation with human intuition to solve structural biology puzzles unattainable through traditional methods.^[85] Its model of distributed volunteering has influenced projects in drug discovery and materials science, underscoring the value of crowdsourced computation in expediting innovations with broad economic implications for faster therapeutic development.^[83] Looking ahead, Rosetta@home is increasingly focusing on generating vast datasets from volunteer simulations to train AI models like RoseTTAFold, addressing global challenges such as antimicrobial resistance and sustainable materials design through enhanced predictive accuracy.^[31] This evolution positions the project as a key resource for integrating human and machine intelligence in tackling pressing biomedical needs.^[82]

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[20]
Applications
### Summary of Applications and Hardware Requirements
[21]
What the Rosetta Protein Modeling Suite Can Do for You - PMC
Mar 17, 2010 · During the sequence optimization step, a Monte Carlo simulated annealing search is used to sample the sequence space. Every amino acid is ...
[22]
Advances in Rosetta protein structure prediction on massively ...
The availability of hundred-teraflop, and shortly, petaflop, computing resources is revolutionizing the approaches available for protein structure prediction.
[23]
https://dl.acm.org/doi/abs/10.5555/1375990.1375992
[24]
The dual role of fragments in fragment-assembly methods for de ...
“Rosetta ab initio” is a fragment-assembly technique for de novo structure prediction that has performed well in the Critical Assessment of Protein Structure ...
[25]
Experimentally-Driven Protein Structure Modeling - PMC
Advantages and limiations of experimental structure determination techniques. Technique, Advantages, Limitations. X-ray crystallography, Large proteins and ...Computational Modeling · Pairwise Constraints-Based... · Conflicting And ``dirty''...
[26]
Structure prediction for CASP7 targets using extensive all-atom ...
We describe predictions made using the Rosetta structure prediction methodology for both template-based modeling and free modeling categories in the Seventh ...
[27]
Protein structure prediction using Rosetta in CASP12 - PMC - NIH
The authors thank Darwin Alonso for developing the computational and network infrastructure and Rosetta@home participants for providing the computing resources ...
[28]
Machine learning generates custom enzymes - Baker Lab
Feb 22, 2023 · The new light-emitting enzymes, called luciferases, can recognize specific chemical substrates and catalyze the emission of photons very efficiently.Missing: Rosetta | Show results with:Rosetta
[29]
[PDF] Computational protein design enables a novel one-carbon ...
This enzyme enables the construction of a new pathway, the formolase pathway, in which formate is converted into the central metabolite dihydroxyacetone phos-.
[30]
Rosetta@home
Looking ahead, Rosetta@home will be an invaluable platform for large-scale virtual screening and peptide simulations for drug discovery. We plan to launch more ...Here · Login · Server Status · Quick guide to Rosetta and its...Missing: official | Show results with:official
[31]
ROSETTA-informed design of structurally stabilized cyclic anti ... - NIH
Oct 25, 2019 · Abstract. β-amyloid oligomers are thought to be the most toxic species formed en route to fibril deposition in Alzheimer's disease.
[32]
Ensemble-based design of tau to inhibit aggregation while ...
We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, and cell models to design tau sequences that ...
[33]
A model of anthrax toxin lethal factor bound to protective antigen
Nov 8, 2005 · The Rosetta-Dock model of the LFN-PA dimer complex lies in a deep energy funnel. Three thousand independent trajectories were carried out, ...
[34]
The RosettaDock server for local protein–protein docking - PMC - NIH
RosettaDock is a structure-prediction-based program, which searches the rigid-body and side-chain conformational space of two interacting proteins.
[35]
Modeling Immunity with Rosetta: Methods for Antibody and Antigen ...
Mar 11, 2021 · These tutorials cover antibody structure prediction, docking, and design and antigen design strategies, including the addition of glycans in Rosetta.
[36]
Vaccination induces broadly neutralizing antibody precursors to HIV ...
May 30, 2024 · HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. ... design in Rosetta: recent methods ...
[37]
Optimization of a Plasmodium falciparum circumsporozoite protein ...
Jan 27, 2020 · (A) Rosetta structure predictions showing poly-NPNA of various lengths on the exposed loop (NPNAx3 circled). (B) Overlaid, minimum energy ...Abstract · Sign Up For Pnas Alerts · Results
[38]
The PfRCR complex bridges malaria parasite and erythrocyte during ...
Dec 20, 2023 · We employed a Rosetta-based, structure-guided approach to design five disulfide bonds that we predicted would hold together the N- and C- ...
[39]
PR > 보도자료 > SK bioscience COVID-19 Vaccine Granted ...
Jun 19, 2023 · SKYCovione is also the world's first medicine developed using computational protein design, an approach that uses Rosetta software to engineer ...
[40]
Design of high-affinity binders to immune modulating receptors for ...
Feb 26, 2025 · While we used Rosetta interface design methods primarily in this paper, the 5HCS scaffolds should provide excellent starting points for ...
[41]
An iterative computational design approach to increase the thermal ...
Jul 9, 2018 · We generate thirteen PDC variants using the Rosetta protein design software. We measure thermal stability of the wild-type PDC and PDC variants ...Missing: clean | Show results with:clean
[42]
https://biotechnologyforbiofuels.biomedcentral.com/articles/10.1186/s13068-018-1178-9
[43]
De novo design of self-assembling helical protein filaments - Science
Nov 9, 2018 · We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins ...
[44]
Design of multi-scale protein complexes by hierarchical building ...
Apr 16, 2021 · There has been considerable recent progress in designing self-assembling protein nano structures and materials mediated by non-covalent protein– ...
[45]
https://www.nature.com/articles/s41467-021-22276-z
[46]
Rosetta@home Update
Mar 4, 2025 · Recently, we have developed a virtual screening protocol in Rosetta, named RosettaVS, for small molecule drug discovery. This work has been ...
[47]
Comprehensive computational design of ordered peptide macrocycles
Dec 15, 2017 · Macrocyclic peptides have diverse properties, including antibiotic and anticancer activities. This makes them good therapeutic leads, ...
[48]
Rosetta@home Research Updates - Baker Lab
Jun 16, 2016 · 3) We can now design peptides that are cyclized via a peptide bond between their N- and C-terminus. Cyclic peptides provide increased resistance ...
[49]
Rosetta Commons – The hub for Rosetta modeling software.
Rosetta Commons drives innovation in biomolecular modeling and design through cutting-edge computational methods and shared software.Missing: 2024 small
[50]
Biomolecular Modeling and Design with Rosetta and ML Tools ...
Biomolecular Modeling and Design with Rosetta and ML Tools Workshop. November 17th – 19th, 2025. For materials from previous workshops, ...Missing: AI integration hybrid
[51]
RosettaScripts: A Scripting Language Interface to the Rosetta ...
RosettaScripts is an XML-like language for specifying modeling tasks in the Rosetta framework. RosettaScripts provides access to protocol-level functionalities.
[52]
Algorithm discovery by protein folding game players - PMC - NIH
Foldit recruits online gamers to optimize the computed Rosetta energy using human spatial problem-solving skills. Players manipulate protein structures with a ...
[53]
Introducing Foldit Education Mode | Nature Structural & Molecular ...
Aug 17, 2020 · With many classrooms staying in remote mode this autumn, Foldit Education Mode offers a unique and free online option for classes worldwide and ...Missing: v2 | Show results with:v2
[54]
Accurate prediction of protein structures and interactions using a ...
Aug 19, 2021 · RoseTTAFold has been evaluated since 15 May 2021 on CAMEO; over the 69 medium and hard targets released during this time (15 May 2021 to 19 June ...
[55]
RoseTTAFold: Accurate protein structure prediction accessible to all
Jul 15, 2021 · With RoseTTAFold, a protein structure can be computed in as little as ten minutes on a single gaming computer. This work was led by Baker lab ...
[56]
De novo protein design by citizen scientists - Nature
Jun 5, 2019 · We posed the challenge of de novo protein design in the online protein-folding game Foldit 5. Players were presented with a fully extended peptide chain.
[57]
Multistate and functional protein design using RoseTTAFold ... - Nature
Sep 25, 2024 · We developed ProteinGenerator (PG), a sequence space diffusion model based on RoseTTAFold that simultaneously generates protein sequences and structures.
[58]
FAH on BOINC - Folding@home
BOINC is an infrastructure for doing distributed computing. BOINC is produced by the same group at LBNL which has done SETI@Home and has become a useful tool ...Missing: volunteer | Show results with:volunteer
[59]
Dig deeper - Folding@home
One aspect that makes Folding@home different from some other distributed computing projects (Rosetta@home, for example) is that we want to see how the car ...Missing: differences similarities
[60]
Rosetta@Home | Science | AAAS
Apr 30, 2010 · It's run from David Baker's lab at the University of Washington, and has users all over the world contributing. A reader sends along news ...Missing: paper founding
[61]
Folding@home Assembles an Exaflop to Fight COVID-19
Apr 1, 2020 · Folding@home amassed donations of more than 1.5 exaflops in computing power to fight COVID-19.
[62]
SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening ...
Jun 28, 2020 · A) The growth of Folding@home (F@H) in response to COVID-19. The cumulative number of users is shown in blue and COVID-19 cases are shown in ...
[63]
Volunteers rally to Rosetta@Home to stop COVID-19
Mar 26, 2020 · Baker Lab · Bhardwaj Lab · DiMaio Lab · King Lab. People. Faculty and Staff ... Rosetta@Home operates on the Berkeley Open Infrastructure for ...
[64]
Homology modeling in the time of collective and artificial intelligence
Folding@Home and Rosetta@Home are examples of crowd-sourcing initiatives where the community is sharing computational resources, whereas RosettaCommons is ...
[65]
[PDF] De novo protein design by citizen scientists - Baker Lab
Players compete to build a model with the lowest free energy, as calculated using the Rosetta energy function11. In the past, Foldit has been primarily applied ...
[66]
World Community Grid | IBM
World Community Grid went online in 2004 with a mission to tackle society's challenges by harnessing the world's spare computing power.
[67]
Scientists from Different Fields Line Up to Join the BOINC Family
Aug 24, 2004 · Furthest along in the process is a team of biophysicists who on June 4 launched their BOINC-based program predictor@home. Its purpose is to ...Missing: history | Show results with:history
[68]
BOINC in Retrospect - David P. Anderson
BOINC is a software system for volunteer computing: it lets people donate time on their home computers and smartphones to science research projects.
[69]
https://www.planetary.org/articles/setiathome_20040824
[70]
Join Rosetta@home
Join Rosetta@home. I'm new | I'm a BOINC user. Download the BOINC desktop software. Download. For Android devices, download BOINC from the Google Play Store or ...Missing: volunteer | Show results with:volunteer
[71]
Rosetta@home: Help the Fight Against COVID-19 With Your Linux ...
Oct 29, 2020 · The BOINC distributed computing platform with which you can access Rosetta@home is available on a 64bit operating system such as Windows, Linux, ...
[72]
Statistics and leaderboards - Rosetta@home
Statistics for Rosetta@home: Top participants · Top teams · Top computers · CPU models. More detailed statistics for Rosetta@home and other BOINC-based ...
[73]
Badges - Rosetta@home
Sep 14, 2017 · Badges for recognition of levels of work completed can be a positive recognition of work completed and machines committed.Tells us your thoughts on granting credit for large protein, long ...What do credits represent? - Rosetta@homeMore results from boinc.bakerlab.org
[74]
Protein sequence design by conformational landscape optimization
We thank Luki Goldschmidt for computational support and also acknowledge the contributions of Rosetta@home volunteers. Supporting Information. Appendix (PDF).
[75]
Message boards - Rosetta@home
Message boards, questions and answers, teams, profiles, user search, user of the day, certificate, site, site search, languages.
[76]
https://boinc.bakerlab.org/rosetta/forum_index.php
[77]
Rosetta@home Rallies a Legion of Computers Against ... - HPCwire
Mar 24, 2020 · Rosetta@home, much like Folding@home, is a massive network of volunteer computers that allows citizen scientists to commit their computers' CPUs ...
[78]
Energy consumption from crunching using Rosetta@Home on my Mac
May 13, 2020 · My only concern is that the heavy CPU/GPU usage on my laptop will use excessive amounts of energy causing my electricity bill to be astronomical ...Missing: challenges | Show results with:challenges
[79]
https://forums.balena.io/t/energy-consumption-from-crunching-using-rosetta-home-on-my-mac/112984
[80]
Introducing Foldit Education Mode - PMC - PubMed Central
Here we introduce Foldit Education Mode, in which students proceed through a self-guided tutorial of standard concepts in protein biochemistry, via a series of ...
[81]
Macromolecular modeling and design in Rosetta - NIH
Here we review tools developed in the last five years, including over 80 methods. We discuss improvements to the score function, user interfaces, and usability.
[82]
Crowd science: The organization of scientific research in open ...
A critical feature of Rosetta@home was a visual interface that showed proteins as they folded. Although the volunteers were meant to contribute only ...
[83]
https://www.sciencedirect.com/science/article/pii/S0048733313001212
[84]
The power of many | Nature Biotechnology
Mar 9, 2011 · The first volunteer computing projects in life sciences were Screensaver Lifesaver and Folding@Home, both launched in 2000. ... Rosetta@home.