[email protected]

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Template:Infobox distributed computing project [email protected] is a distributed computing project for protein structure prediction on the Berkeley Open Infrastructure for Network Computing (BOINC) platform, run by the Baker laboratory at the University of Washington. [email protected] aims to predict protein–protein docking and design new proteins with the help of about sixty thousand active volunteered computers processing at over 210 teraFLOPS on average as of July 29, 2016.<ref name="BOINCstats_RosettaOverview">Template:Cite web</ref> Foldit, a [email protected] videogame, aims to reach these goals with a crowdsourcing approach. Though much of the project is oriented toward basic research to improve the accuracy and robustness of proteomics methods, [email protected] also does applied research on malaria, Alzheimer's disease, and other pathologies.<ref>Template:Cite web</ref>

Like all BOINC projects, [email protected] uses idle computer processing resources from volunteers' computers to perform calculations on individual workunits. Completed results are sent to a central project server where they are validated and assimilated into project databases. The project is cross-platform, and runs on a wide variety of hardware configurations. Users can view the progress of their individual protein structure prediction on the [email protected] screensaver.

In addition to disease-related research, the [email protected] network serves as a testing framework for new methods in structural bioinformatics. Such methods are then used in other Rosetta-based applications, like RosettaDock and the Human Proteome Folding Project, after being sufficiently developed and proven stable on [email protected]'s large and diverse set of volunteer computers. Two especially important tests for the new methods developed in [email protected] are the Critical Assessment of Techniques for Protein Structure Prediction (CASP) and Critical Assessment of Prediction of Interactions (CAPRI) experiments, biannual experiments which evaluate the state of the art in protein structure prediction and protein–protein docking prediction, respectively. [email protected] consistently ranks among the foremost docking predictors, and is one of the best tertiary structure predictors available.<ref name="CAPRI3">Template:Cite journal</ref>

Computing platform

Template:See also

The [email protected] application and the BOINC distributed computing platform are available for the operating systems Windows, Linux, and macOS; BOINC also runs on several others, e.g., FreeBSD.<ref name="BOINCClient">Template:Cite web</ref> Participation in [email protected] requires a central processing unit (CPU) with a clock speed of at least 500 MHz, 200 megabytes of free disk space, 512 megabytes of physical memory, and Internet connectivity.<ref>Template:Cite web</ref> As of July 20, 2016, the current version of the Rosetta Mini application is 3.73.<ref name="oldNews">Template:Cite web</ref> The current recommended BOINC program version is 7.6.22.<ref name="BOINCClient"/> Standard Hypertext Transfer Protocol (HTTP) (port 80) is used for communication between the user's BOINC client and the [email protected] servers at the University of Washington; HTTPS (port 443) is used during password exchange. Remote and local control of the BOINC client use port 31416 and port 1043, which might need to be specifically unblocked if they are behind a firewall.<ref>Template:Cite web</ref> Workunits containing data on individual proteins are distributed from servers located in the Baker lab at the University of Washington to volunteers' computers, which then calculate a structure prediction for the assigned protein. To avoid duplicate structure predictions on a given protein, each workunit is initialized with a random seed number. This gives each prediction a unique trajectory of descent along the protein's energy landscape.<ref>Template:Cite web</ref> Protein structure predictions from [email protected] are approximations of a global minimum in a given protein's energy landscape. That global minimum represents the most energetically favorable conformation of the protein, i.e., its native state.

File:[email protected] v1.32 screensaver.png
[email protected] screensaver, showing the progress of a structure prediction for a synthetic ubiquitin protein (PDB ID: 1ogw)

A primary feature of the [email protected] graphical user interface (GUI) is a screensaver which shows a current workunit's progress during the simulated protein folding process. In the upper-left of the current screensaver, the target protein is shown adopting different shapes (conformations) in its search for the lowest energy structure. Depicted immediately to the right is the structure of the most recently accepted. On the upper right the lowest energy conformation of the current decoy is shown; below that is the true, or native, structure of the protein if it has already been determined. Three graphs are included in the screensaver. Near the middle, a graph for the accepted model's thermodynamic free energy is displayed, which fluctuates as the accepted model changes. A graph of the accepted model's root-mean-square deviation (RMSD), which measures how structurally similar the accepted model is to the native model, is shown far right. On the right of the accepted energy graph and below the RMSD graph, the results from these two functions are used to produce an energy vs. RMSD plot as the model is progressively refined.<ref>Template:Cite web</ref>

Like all BOINC projects, [email protected] runs in the background of the user's computer, using idle computer power, either at or before logging into an account on the host operating system. The program frees resources from the CPU as they are needed by other applications so that normal computer use is unaffected. Many program settings can be specified via user account preferences, including: the maximum percentage of CPU resources the program can use (to control power consumption or heat production from a computer running at sustained capacity), the times of day during which the program can run, and many more.

Rosetta, the software that runs on the [email protected] network, was rewritten in C++ to allow easier development than that allowed by its original version, which was written in Fortran. This new version is object-oriented, and was released on February 8, 2008.<ref name="oldNews"/><ref>Template:Cite web</ref> Development of the Rosetta code is done by Rosetta Commons.<ref name="rosettaCommons">Template:Cite web</ref> The software is freely licensed to the academic community and available to pharmaceutical companies for a fee.<ref name="rosettaCommons"/>

Project significance

Template:Further

With the proliferation of genome sequencing projects, scientists can infer the amino acid sequence, or primary structure, of many proteins that carry out functions within the cell. To better understand a protein's function and aid in rational drug design, scientists need to know the protein's three-dimensional tertiary structure.

File:T0281-bakerprediction overlay.png
CASP6 target T0281, the first ab initio protein structure prediction to approach atomic-level resolution. Rosetta produced a model for T0281 (superpositioned in magenta) 1.5 Ångström (Å) RMSD from the crystal structure (blue).

Protein 3D structures are currently determined experimentally via X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy. The process is slow (it can take weeks or even months to figure out how to crystallize a protein for the first time) and costly (around $100,000 USD per protein).<ref>Template:Cite book</ref> Unfortunately, the rate at which new sequences are discovered far exceeds the rate of structure determination – out of more than 7,400,000 protein sequences available in the National Center for Biotechnology Information (NCBI) nonredundant (nr) protein database, fewer than 52,000 proteins' 3D structures have been solved and deposited in the Protein Data Bank, the main repository for structural information on proteins.<ref>Template:Cite web</ref> One of the main goals of [email protected] is to predict protein structures with the same accuracy as existing methods, but in a way that requires significantly less time and money. [email protected] also develops methods to determine the structure and docking of membrane proteins (e.g., G protein–coupled receptors (GPCRs)),<ref>Template:Cite web</ref> which are exceptionally difficult to analyze with traditional techniques like X-ray crystallography and NMR spectroscopy, yet represent the majority of targets for modern drugs.

Progress in protein structure prediction is evaluated in the biannual Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiment, in which researchers from around the world attempt to derive a protein's structure from the protein's amino acid sequence. High scoring groups in this sometimes competitive experiment are considered the de facto standard-bearers for what is the state of the art in protein structure prediction. Rosetta, the program on which [email protected] is based, has been used since CASP5 in 2002. In the 2004 CASP6 experiment, Rosetta made history by being the first to produce a close to atomic-level resolution, ab initio protein structure prediction in its submitted model for CASP target T0281.<ref name="[email protected]_ResearchOverview">Template:Cite web</ref> Ab initio modeling is considered an especially difficult category of protein structure prediction, as it does not use information from structural homology and must rely on information from sequence homology and modeling physical interactions within the protein. [email protected] has been used in CASP since 2006, where it was among the top predictors in every category of structure prediction in CASP7.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="CASP7Assessment">Template:Cite journal</ref> These high quality predictions were enabled by the computing power made available by [email protected] volunteers.<ref name="CASP7_baker">Template:Cite journal</ref> Increasing computing power allows [email protected] to sample more regions of conformation space (the possible shapes a protein can assume), which, according to Levinthal's paradox, is predicted to increase exponentially with protein length.

[email protected] is also used in protein–protein docking prediction, which determines the structure of multiple complexed proteins, or quaternary structure. This type of protein interaction affects many cellular functions, including antigen–antibody and enzyme–inhibitor binding and cellular import and export. Determining these interactions is critical for drug design. Rosetta is used in the Critical Assessment of Prediction of Interactions (CAPRI) experiment, which evaluates the state of the protein docking field similar to how CASP gauges progress in protein structure prediction. The computing power made available by [email protected]'s project volunteers has been cited as a major factor in Rosetta's performance in CAPRI, where its docking predictions have been among the most accurate and complete.<ref name="CAPRI3_1">Template:Cite journal</ref>

In early 2008, Rosetta was used to computationally design a protein with a function never before observed in nature.<ref name="RetroAldol">Template:Cite journal</ref> This was inspired in part by the retraction of a high-profile paper from 2004 which originally described the computational design of a protein with improved enzymatic activity relative to its natural form.<ref>Template:Cite journal</ref> The 2008 research paper from David Baker's group describing how the protein was made, which cited [email protected] for the computing resources it made available, represented an important proof of concept for this protein design method.<ref name="RetroAldol"/> This type of protein design could have future applications in drug discovery, green chemistry, and bioremediation.<ref name="RetroAldol"/>

Disease-related research

In addition to basic research in predicting protein structure, docking and design, [email protected] is also used in immediate disease-related research.<ref name="medicalRelevance">Template:Cite web</ref> Numerous minor research projects are described in David Baker's [email protected] journal.<ref>Template:Cite web</ref> As of February 2014, information on recent publications and a short description of the work are being updated on the forum.<ref>Template:Cite web</ref>

Alzheimer's disease

A component of the Rosetta software suite, RosettaDesign, was used to accurately predict which regions of amyloidogenic proteins were most likely to make amyloid-like fibrils.<ref>Template:Cite journal</ref> By taking hexapeptides (six amino acid-long fragments) of a protein of interest and selecting the lowest energy match to a structure similar to that of a known fibril forming hexapeptide, RosettaDesign was able to identify peptides twice as likely to form fibrils as are random proteins.<ref>Template:Cite journal</ref> [email protected] was used in the same study to predict structures for amyloid beta, a fibril-forming protein that has been postulated to cause Alzheimer's disease.<ref>Template:Cite web</ref> Preliminary but as yet unpublished results have been produced on Rosetta-designed proteins that may prevent fibrils from forming, although it is unknown whether it can prevent the disease.<ref>Template:Cite web</ref>

Anthrax

Another component of Rosetta, RosettaDock,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Schueler-Furman">Template:Cite journal</ref> was used in conjunction with experimental methods to model interactions between three proteins—lethal factor (LF), edema factor (EF) and protective antigen (PA)—that make up anthrax toxin. The computer model accurately predicted docking between LF and PA, helping to establish which domains of the respective proteins are involved in the LF–PA complex. This insight was eventually used in research resulting in improved anthrax vaccines.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Herpes simplex virus 1

RosettaDock was used to model docking between an antibody (immunoglobulin G) and a surface protein expressed by the cold sore virus, herpes simplex virus 1 (HSV-1) which serves to degrade the antiviral antibody. The protein complex predicted by RosettaDock closely agreed with the especially difficult-to-obtain experimental models, leading researchers to conclude that the docking method has potential to address some of the problems that X-ray crystallography has with modeling protein–protein interfaces.<ref>Template:Cite journal</ref>

HIV

As part of research funded by a $19.4 million grant by the Bill & Melinda Gates Foundation,<ref>Template:Cite news</ref> [email protected] has been used in designing multiple possible vaccines for human immunodeficiency virus (HIV).<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Malaria

In research involved with the Grand Challenges in Global Health initiative,<ref>Template:Cite web</ref> Rosetta has been used to computationally design novel homing endonuclease proteins, which could eradicate Anopheles gambiae or otherwise render the mosquito unable to transmit malaria.<ref>Template:Cite journal</ref> Being able to model and alter protein–DNA interactions specifically, like those of homing endonucleases, gives computational protein design methods like Rosetta an important role in gene therapy (which includes possible cancer treatments).<ref name="medicalRelevance"/><ref>Template:Cite journal</ref>

Development history and branches

Originally introduced by the Baker laboratory in 1998 as an ab initio approach to structure prediction,<ref>Template:Cite journal</ref> Rosetta has since branched into several development streams and distinct services. The Rosetta platform derives its name from the Rosetta Stone, as it attempts to decipher the structural "meaning" of proteins' amino acid sequences.<ref>Template:Cite web</ref> More than seven years after Rosetta's first appearance, the [email protected] project was released (i.e., announced as no longer beta) on October 6, 2005.<ref name="oldNews"/> Many of the graduate students and other researchers involved in Rosetta's initial development have since moved to other universities and research institutions, and subsequently enhanced different parts of the Rosetta project.

RosettaDesign

File:TOP7-rosetta superposition.png
Superposition of Rosetta-designed model (red) for Top7 onto its X-ray crystal structure (blue, PDB ID: 1QYS)

RosettaDesign, a computing approach to protein design based on Rosetta, began in 2000 with a study in redesigning the folding pathway of Protein G.<ref>Template:Cite journal</ref> In 2002 RosettaDesign was used to design Top7, a 93-amino acid long α/β protein that had an overall fold never before recorded in nature. This new conformation was predicted by Rosetta to within 1.2 Å RMSD of the structure determined by X-ray crystallography, representing an unusually accurate structure prediction.<ref>Template:Cite journal</ref> Rosetta and RosettaDesign earned widespread recognition by being the first to design and accurately predict the structure of a novel protein of such length, as reflected by the 2002 paper describing the dual approach prompting two positive letters in the journal Science,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and being cited by more than 240 other scientific articles.<ref>Template:Cite web</ref> The visible product of that research, Top7, was featured as the RCSB PDB's 'Molecule of the Month' in October 2006;<ref>Template:Cite web</ref> a superposition of the respective cores (residues 60–79) of its predicted and X-ray crystal structures are featured in the [email protected] logo.<ref name="[email protected]_ResearchOverview"/>

Brian Kuhlman, a former postdoctoral associate in David Baker's lab and now an associate professor at the University of North Carolina, Chapel Hill,<ref>Template:Cite web</ref> offers RosettaDesign as an online service.<ref>Template:Cite web</ref>

RosettaDock

RosettaDock was added to the Rosetta software suite during the first CAPRI experiment in 2002 as the Baker laboratory's algorithm for protein–protein docking prediction.<ref name="CAPRI_1">Template:Cite journal</ref> In that experiment, RosettaDock made a high-accuracy prediction for the docking between streptococcal pyogenic exotoxin A and a T cell-receptor β-chain, and a medium accuracy prediction for a complex between porcine α-amylase and a camelid antibody. While the RosettaDock method only made two acceptably accurate predictions out of seven possible, this was enough to rank it seventh out of nineteen prediction methods in the first CAPRI assessment.<ref name="CAPRI_1"/>

Development of RosettaDock diverged into two branches for subsequent CAPRI rounds as Jeffrey Gray, who laid the groundwork for RosettaDock while at the University of Washington, continued working on the method in his new position at Johns Hopkins University. Members of the Baker laboratory further developed RosettaDock in Gray's absence. The two versions differed slightly in side-chain modeling, decoy selection and other areas.<ref name="Schueler-Furman"/><ref>Template:Cite journal</ref> Despite these differences, both the Baker and Gray methods performed well in the second CAPRI assessment, placing fifth and seventh respectively out of 30 predictor groups.<ref>Template:Cite journal</ref> Jeffrey Gray's RosettaDock server is available as a free docking prediction service for non-commercial use.<ref>Template:Cite web</ref>

In October 2006, RosettaDock was integrated into [email protected] The method used a fast, crude docking model phase using only the protein backbone. This was followed by a slow full-atom refinement phase in which the orientation of the two interacting proteins relative to each other, and side-chain interactions at the protein–protein interface, were simultaneously optimized to find the lowest energy conformation.<ref>Template:Cite web</ref> The vastly increased computing power afforded by the [email protected] network, combined with revised fold-tree representations for backbone flexibility and loop modeling, made RosettaDock sixth out of 63 prediction groups in the third CAPRI assessment.<ref name="CAPRI3"/><ref name="CAPRI3_1"/>

Robetta

The Robetta server is an automated protein structure prediction service offered by the Baker laboratory for non-commercial ab initio and comparative modeling.<ref>Template:Cite web</ref> It has participated as an automated prediction server in the biannual CASP experiments since CASP5 in 2002, performing among the best in the automated server prediction category.<ref>Template:Cite journal</ref> Robetta has since competed in CASP6 and 7, where it did better than average among both automated server and human predictor groups.<ref name="CASP7Assessment"/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

In modeling protein structure as of CASP6, Robetta first searches for structural homologs using BLAST, PSI-BLAST, and 3D-Jury, then parses the target sequence into its individual domains, or independently folding units of proteins, by matching the sequence to structural families in the Pfam database. Domains with structural homologs then follow a "template-based model" (i.e., homology modeling) protocol. Here, the Baker laboratory's in-house alignment program, K*sync, produces a group of sequence homologs, and each of these is modeled by the Rosetta de novo method to produce a decoy (possible structure). The final structure prediction is selected by taking the lowest energy model as determined by a low-resolution Rosetta energy function. For domains that have no detected structural homologs, a de novo protocol is followed in which the lowest energy model from a set of generated decoys is selected as the final prediction. These domain predictions are then connected together to investigate inter-domain, tertiary-level interactions within the protein. Finally, side-chain contributions are modeled using a protocol for Monte Carlo conformational search.<ref>Template:Cite journal</ref>

In CASP8, Robetta was augmented to use Rosetta's high resolution all-atom refinement method,<ref>Template:Cite web</ref> the absence of which was cited as the main cause for Robetta being less accurate than the [email protected] network in CASP7.<ref name="CASP7_baker"/>

Foldit

Template:See also On May 9, 2008, after [email protected] users suggested an interactive version of the distributed computing program, the Baker lab publicly released Foldit, an online protein structure prediction game based on the Rosetta platform.<ref>Template:Cite web</ref> Template:As of, Foldit has over 59,000 registered users.<ref>Template:Cite web</ref> The game gives users a set of controls (e.g., shake, wiggle, rebuild) to manipulate the backbone and amino acid side chains of the target protein into more energetically favorable conformations. Users can work on solutions individually as soloists or collectively as evolvers, accruing points under either category as they improve their structure predictions.<ref>Template:Cite web</ref> Users can also individually compete with other users via a duel feature, in which the player with the lowest energy structure after 20 moves wins.

Comparison to similar distributed computing projects

There are several distributed computed projects which have study areas similar to those of [email protected], but differ in their research approach:

[email protected]

Of all the major distributed computing projects involved in protein research, [email protected] is the only one not using the BOINC platform.<ref>Template:Cite web </ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref> Both [email protected] and [email protected] study protein misfolding diseases such as Alzheimer's disease, but [email protected] does so much more exclusively.<ref>Template:Cite web</ref><ref>Template:Cite web</ref> [email protected] almost exclusively uses all-atom molecular dynamics models to understand how and why proteins fold (or potentially misfold, and subsequently aggregate to cause diseases).<ref>Template:Cite web</ref><ref name="why fold">Template:Cite web</ref> In other words, [email protected]'s strength is modeling the process of protein folding, while [email protected]'s strength is computing protein design and predicting protein structure and docking.

Some of [email protected]'s results are used as the basis for some [email protected] projects. Rosetta provides the most likely structure, but it is not definite if that is the form the molecule takes or whether or not it is viable. [email protected] can then be used to verify [email protected]'s results, and can provide added atomic-level information, and details of how the molecule changes shape.<ref name="why fold"/><ref>Template:Cite web</ref>

The two projects also differ significantly in their computing power and host diversity. Averaging about 6,650 teraFLOPS from a host base of central processing units (CPUs), graphics processing units (GPUs), and PS3s,<ref>Template:Cite web</ref> [email protected] has nearly 108 times more computing power than [email protected]<ref name="BOINCstats_RosettaOverview"/>

World Community Grid

Both Phase I and Phase II of the Human Proteome Folding Project (HPF), a subproject of World Community Grid, have used the Rosetta program to make structural and functional annotations of various genomes.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> Although he now uses it to create databases for biologists, Richard Bonneau, head scientist of the Human Proteome Folding Project, was active in the original development of Rosetta at David Baker's laboratory while obtaining his PhD.<ref>Template:Cite web</ref> More information on the relationship between the HPF1, HPF2 and [email protected] can be found on Richard Bonneau's website.<ref>Template:Cite web</ref>

[email protected]

Like [email protected], [email protected] specialized in protein structure prediction.<ref>Template:Cite webTemplate:Dead link</ref> While [email protected] uses the Rosetta program for its structure prediction, [email protected] used the dTASSER methodology.<ref>Template:Cite web</ref> In 2009, [email protected] shut down.

Other protein related distributed computing projects on BOINC include [email protected], [email protected], [email protected], SIMAP, and TANPAKU. [email protected], the [email protected] alpha project which tests new application versions, work units, and updates before they move on to [email protected], runs on BOINC also.<ref>Template:Cite web</ref>

Volunteer contributions

[email protected] depends on computing power donated by individual project members for its research. Template:As of, about 26,900 users from 150 countries were active members of [email protected], together contributing idle processor time from about 66,000 computers for a combined average performance of over 83 teraFLOPS.<ref name="BOINCstats_RosettaOverview"/>

File:Boincstats [email protected] CpD.gif
Bar chart showing cumulative credit per day for [email protected] over a 60-day period, indicating its computing power during the CASP8 experiment

Users are granted BOINC credits as a measure of their contribution. The credit granted for each workunit is the number of decoys produced for that workunit multiplied by the average claimed credit for the decoys submitted by all computer hosts for that workunit. This custom system was designed to address significant differences between credit granted to users with the standard BOINC client and an optimized BOINC client, and credit differences between users running [email protected] on Windows and Linux operating systems.<ref>Template:Cite web</ref> The amount of credit granted per second of CPU work is lower for [email protected] than most other BOINC projects.<ref name="pcp">Template:Cite web</ref> [email protected] is thirteenth out of over 40 BOINC projects in terms of total credit.<ref>Template:Cite web</ref>

[email protected] users who predict protein structures submitted for the CASP experiment are acknowledged in scientific publications regarding their results.<ref name="CASP7_baker"/> Users who predict the lowest energy structure for a given workunit are featured on the [email protected] homepage as Predictor of the Day, along with any team of which they are a member.<ref>Template:Cite web</ref> A User of the Day is chosen randomly each day to be on the homepage also, from among users who have made a [email protected] profile.<ref>Template:Cite web</ref>

References

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External links

Online Rosetta services

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