Folding@home
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Folding@home
Original author(s) Vijay Pande
Developer(s) Pande Laboratory, Sony, Nvidia, ATI
Technologies, Joseph Coffland, Cauldron
Development[1]
Initial release October 1, 2000; 21 years ago
Stable release 7.6.21 / October 23, 2020; 18 months ago[2]
Operating system Microsoft Windows, macOS, Linux, PlayStation
3 (discontinued as of firmware version 4.30)
Platform IA-32, x86-64, ARM64, CUDA[3]
Available in English, French, Spanish, Swedish
Type Distributed computing
License Proprietary software[4]
Website foldingathome.org
Folding@home (FAH or F@h) is a distributed computing project aimed to help
scientists develop new therapeutics for a variety of diseases by the means of
simulating protein dynamics. This includes the process of protein folding and the
movements of proteins, and is reliant on simulations run on volunteers' personal
computers.[5] Folding@home is currently based at Washington University in St.
Louis and led by Greg Bowman, a former student of Vijay Pande.[6]
The project utilizes graphics processing units (GPUs), central processing
units (CPUs), and ARM processors like those on the Raspberry Pi for distributed
computing and scientific research. The project uses
statistical simulation methodology that is a paradigm shift from traditional computing
methods.[7] As part of the client–server model network architecture, the volunteered
machines each receive pieces of a simulation (work units), complete them, and
return them to the project's database servers, where the units are compiled into an
overall simulation. Volunteers can track their contributions on the Folding@home
website, which makes volunteers' participation competitive and encourages long-
term involvement.
Folding@home is one of the world's fastest computing systems. With heightened
interest in the project as a result of the COVID-19 pandemic,[8] the system achieved a
speed of approximately 1.22 exaflops by late March 2020 and reached 2.43 exaflops
by April 12, 2020,[9] making it the world's first exaflop computing system. This level of
performance from its large-scale computing network has allowed researchers to
run computationally costly atomic-level simulations of protein folding thousands of
times longer than formerly achieved. Since its launch on October 1, 2000,
Folding@home was involved in the production of 226 scientific research papers.
[10]
Results from the project's simulations agree well with experiments. [11][12][13]
Contents
1Background
2Examples of application in biomedical research
o 2.1Alzheimer's disease
o 2.2Huntington's disease
o 2.3Cancer
o 2.4Osteogenesis imperfecta
o 2.5Viruses
o 2.6Drug design
3Potential applications in biomedical research
o 3.1Prion diseases
4Patterns of participation
o 4.1Performance
o 4.2Points
5Software
o 5.1Work units
o 5.2Cores
o 5.3Client
5.3.1Graphics processing units
5.3.2PlayStation 3
5.3.3Multi-core processing client
5.3.4V7
5.3.5Google Chrome
5.3.6Android
6Comparison to other molecular simulators
7See also
8References
9Sources
10External links
Background[edit]
Further information: Protein folding
A protein before and after folding. It starts in an unstable random coil state and finishes in its native state
conformation.
Proteins are an essential component to many biological functions and participate in
virtually all processes within biological cells. They often act as enzymes, performing
biochemical reactions including cell signaling, molecular transportation, and cellular
regulation. As structural elements, some proteins act as a type of skeleton for cells,
and as antibodies, while other proteins participate in the immune system. Before a
protein can take on these roles, it must fold into a functional three-dimensional
structure, a process that often occurs spontaneously and is dependent on
interactions within its amino acid sequence and interactions of the amino acids with
their surroundings. Protein folding is driven by the search to find the most
energetically favorable conformation of the protein, i.e., its native state. Thus,
understanding protein folding is critical to understanding what a protein does and
how it works, and is considered a holy grail of computational biology.[14][15] Despite
folding occurring within a crowded cellular environment, it typically proceeds
smoothly. However, due to a protein's chemical properties or other factors, proteins
may misfold, that is, fold down the wrong pathway and end up misshapen. Unless
cellular mechanisms can destroy or refold misfolded proteins, they can
subsequently aggregate and cause a variety of debilitating diseases.[16] Laboratory
experiments studying these processes can be limited in scope and atomic detail,
leading scientists to use physics-based computing models that, when
complementing experiments, seek to provide a more complete picture of protein
folding, misfolding, and aggregation. [17][18]
Due to the complexity of proteins' conformation or configuration space (the set of
possible shapes a protein can take), and limits in computing power, all-atom
molecular dynamics simulations have been severely limited in the timescales that
they can study. While most proteins typically fold in the order of milliseconds, [17]
before 2010, simulations could only reach nanosecond to microsecond timescales.
[19]
General-purpose supercomputers have been used to simulate protein folding, but
[11]
such systems are intrinsically costly and typically shared among many research
groups. Further, because the computations in kinetic models occur serially,
strong scaling of traditional molecular simulations to these architectures is
exceptionally difficult.[20][21] Moreover, as protein folding is a stochastic process (i.e.,
random) and can statistically vary over time, it is challenging computationally to use
long simulations for comprehensive views of the folding process. [22][23]
Folding@home uses Markov state models, like the one diagrammed here, to model the possible shapes
and folding pathways a protein can take as it condenses from its initial randomly coiled state (left) into its
native 3-D structure (right).
Protein folding does not occur in one step.[16] Instead, proteins spend most of their
folding time, nearly 96% in some cases,[24] waiting in various
intermediate conformational states, each a local thermodynamic free
energy minimum in the protein's energy landscape. Through a process known
as adaptive sampling, these conformations are used by Folding@home as starting
points for a set of simulation trajectories. As the simulations discover more
conformations, the trajectories are restarted from them, and a Markov state
model (MSM) is gradually created from this cyclic process. MSMs are discrete-
time master equation models which describe a biomolecule's conformational and
energy landscape as a set of distinct structures and the short transitions between
them. The adaptive sampling Markov state model method significantly increases the
efficiency of simulation as it avoids computation inside the local energy minimum
itself, and is amenable to distributed computing (including on GPUGRID) as it allows
for the statistical aggregation of short, independent simulation trajectories. [25] The
amount of time it takes to construct a Markov state model is inversely proportional to
the number of parallel simulations run, i.e., the number of processors available. In
other words, it achieves linear parallelization, leading to an approximately four orders
of magnitude reduction in overall serial calculation time. A completed MSM may
contain tens of thousands of sample states from the protein's phase space (all the
conformations a protein can take on) and the transitions between them. The model
illustrates folding events and pathways (i.e., routes) and researchers can later use
kinetic clustering to view a coarse-grained representation of the otherwise highly
detailed model. They can use these MSMs to reveal how proteins misfold and to
quantitatively compare simulations with experiments. [7][22][26]
Between 2000 and 2010, the length of the proteins Folding@home has studied have
increased by a factor of four, while its timescales for protein folding simulations have
increased by six orders of magnitude.[27] In 2002, Folding@home used Markov state
models to complete approximately a million CPU days of simulations over the span
of several months,[13] and in 2011, MSMs parallelized another simulation that required
an aggregate 10 million CPU hours of computing.[28] In January 2010, Folding@home
used MSMs to simulate the dynamics of the slow-folding 32-residue NTL9 protein
out to 1.52 milliseconds, a timescale consistent with experimental folding rate
predictions but a thousand times longer than formerly achieved. The model
consisted of many individual trajectories, each two orders of magnitude shorter, and
provided an unprecedented level of detail into the protein's energy landscape. [7][11][29] In
2010, Folding@home researcher Gregory Bowman was awarded the Thomas Kuhn
Paradigm Shift Award from the American Chemical Society for the development of
the open-source MSMBuilder software and for attaining quantitative agreement
between theory and experiment.[30][31] For his work, Pande was awarded the 2012
Michael and Kate Bárány Award for Young Investigators for "developing field-
defining and field-changing computational methods to produce leading theoretical
models for protein and RNA folding",[32] and the 2006 Irving Sigal Young Investigator
Award for his simulation results which "have stimulated a re-examination of the
meaning of both ensemble and single-molecule measurements, making Pande's
efforts pioneering contributions to simulation methodology." [33]
