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. Folding@home is currently based at Washington University in St. Louis Mar 29, · Writing a research paper is one of the most challenging aspects of a student’s life. Throughout and/or in the final stage of college or university, you should write this type of work, ranging from the simplest (monographs, projects), to the most complex (university degrees, masters, doctorates) Our Department of Computing is proud to offer a research-led education environment that values and invests in people. We conduct world-class research and transfer this research into our teaching. Find out more about our strategy, taught courses, research environment, and staff on our welcome page
Folding@home - Wikipedia
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.
Louis and led by Greg Bowman, a former student of Vijay Pande. The project utilizes graphics processing units GPUscentral processing units CPUsand ARM processors like those on the Raspberry Pi for distributed computing and scientific research, distributed computing thesis.
The project uses statistical simulation methodology that is a paradigm shift from traditional computing methods. Volunteers can track their contributions on the Folding home website, distributed computing thesis, 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 pandemic[7] the system achieved a speed of approximately 1. 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, distributed computing thesis,the Pande Lab has produced scientific research papers as a direct result of Folding home, distributed computing thesis. Proteins are an essential component to many biological functions and participate in virtually all processes within biological cells. They often act as enzymesperforming biochemical reactions including cell signalingmolecular transportation, and cellular regulation.
As structural elements, some proteins act as a type of skeleton for cellsand as antibodiesdistributed computing thesis, while other proteins participate in the immune system. Before a protein can take on these roles, it must fold into a functional three-dimensional structurea 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. Thus, understanding protein folding is critical to understanding what a protein does and how it distributed computing thesis, and is considered a holy grail of computational biology. However, due to a protein's chemical properties or other factors, proteins may misfoldthat 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. Due to the complexity of proteins' conformation or configuration space the set of possible shapes a protein can takeand 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, [16] [18] beforesimulations could only reach nanosecond to microsecond timescales. Further, because the computations in kinetic models occur serially, strong scaling of traditional molecular simulations to these architectures is exceptionally difficult.
Protein folding does not occur in one step. Through a process known as adaptive samplingthese 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.
In other words, it achieves linear parallelizationleading 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 distributed computing thesis between them.
The model illustrates folding events and pathways i. They can use these MSMs to reveal how proteins misfold and to quantitatively compare simulations with experiments. Between andthe length of the proteins Folding home has distributed computing thesis have distributed computing thesis by a factor of four, while its timescales for protein folding simulations have increased by distributed computing thesis orders of magnitude.
The model consisted of distributed computing thesis individual trajectories, each two orders of magnitude shorter, and provided an unprecedented level of detail into the protein's energy landscape. Protein misfolding can result in a variety of diseases including Alzheimer's disease, cancerdistributed computing thesis, Creutzfeldt—Jakob diseasecystic fibrosisHuntington's disease, distributed computing thesis anemiadistributed computing thesis, and type II diabetes.
Such therapies include the use of engineered molecules to alter the production of a given protein, help destroy a misfolded protein, or assist in the folding process. The simulations run on Folding home are used in conjunction with laboratory experiments, [21] but researchers can use them to study how folding in vitro differs from folding in native cellular environments. This is advantageous in studying aspects of folding, misfolding, and their relationships to disease that are difficult to observe experimentally.
For example, inFolding home simulated protein folding inside a ribosomal exit tunnel, to help scientists better understand how natural confinement and crowding might influence the folding process. It is not generally known how the denaturant affects the protein's refolding, distributed computing thesis, and it is difficult to experimentally determine if these denatured states contain residual structures which may influence folding behavior.
InFolding home used GPUs to simulate the unfolded states of Protein Land predicted its collapse rate in strong agreement with experimental results. The large data sets from the project are freely available for other researchers to use upon request and some can be accessed from the Folding home website. Alzheimer's disease is an incurable neurodegenerative disease which most often affects the elderly and accounts for more than half of all cases of dementia.
Its exact cause remains unknown, but the disease is identified as a protein misfolding disease, distributed computing thesis. Alzheimer's is associated with toxic aggregations of the amyloid beta Aβ peptidecaused by Aβ misfolding and clumping together with other Aβ peptides. These Aβ aggregates then grow into significantly larger senile plaquesa pathological marker of Alzheimer's disease. Moreover, atomic simulations of Aβ aggregation distributed computing thesis highly demanding computationally due to their size and complexity.
Preventing Aβ aggregation is a promising method to developing therapeutic drugs for Alzheimer's disease, according to Naeem and Fazili in a literature review article. Prior studies were only able to simulate about 10 microseconds. Folding home was able to simulate Aβ folding for six orders of magnitude longer than formerly possible.
Researchers used the results of this study to identify a beta hairpin that was a major source distributed computing thesis molecular interactions within the structure. In DecemberFolding home found several small drug candidates which appear to inhibit the toxicity of Aβ aggregates. Huntington's disease is a neurodegenerative genetic disorder that is associated with protein misfolding and aggregation. Excessive repeats of the glutamine amino acid at the N-terminus of the huntingtin protein cause aggregation, and although the behavior of the repeats is not completely understood, it does lead to the cognitive decline associated with the disease.
More than half of all known cancers involve mutations of p53a tumor suppressor protein present in every cell which regulates the cell cycle and signals for cell death in the event of damage to DNA.
Specific mutations in p53 can disrupt these functions, allowing an abnormal cell to continue growing unchecked, resulting in the development of tumors. Analysis of these mutations helps explain the root causes of prelated cancers. The simulation's results agreed with experimental observations and gave insights into the refolding of the dimer that were formerly unobtainable.
The method was reasonably successful in identifying cancer-promoting mutations and determined the effects of specific mutations which could not otherwise be measured experimentally. Folding home is also used to study protein chaperones[34] heat shock proteins which play essential roles in cell survival by assisting with the folding of other proteins in the crowded and chemically stressful environment within a cell.
Rapidly growing cancer cells rely on specific chaperones, and some chaperones play key roles in chemotherapy resistance.
Inhibitions to these specific chaperones are seen as potential modes of action for efficient chemotherapy distributed computing thesis or for reducing the spread of cancer. Interleukin 2 IL-2 is a protein that helps T cells of the immune system attack pathogens and tumors. However, its use as a cancer treatment is restricted due to serious side effects such as pulmonary edema. IL-2 binds to these pulmonary cells differently than it does to T cells, so IL-2 research involves understanding the differences between these binding mechanisms.
Indistributed computing thesis, Folding home assisted with the discovery of a mutant form of IL-2 which is three hundred times more effective in its immune system role but carries fewer distributed computing thesis effects.
In experiments, this altered form significantly outperformed natural IL-2 in impeding tumor growth, distributed computing thesis. Pharmaceutical companies have expressed interest in the mutant molecule, and the National Institutes of Health are testing it against a large variety of tumor models to try to accelerate its development distributed computing thesis a therapeutic.
Osteogenesis imperfectaknown as brittle bone disease, is an incurable genetic bone disorder which can be lethal. Those with the disease are unable to make functional connective bone tissue. This is most commonly due to a mutation in Type-I collagen[75] which fulfills a variety of structural roles and is the most abundant protein in mammals.
Folding home is assisting in research towards preventing some virusessuch as influenza and HIVfrom recognizing and entering biological cells.
This fusion involves conformational changes of viral fusion proteins and protein docking[35] but the exact molecular mechanisms behind fusion remain largely unknown. This distributed computing thesis limits typical computer simulations to about ten thousand atoms over tens of nanoseconds: a difference of several orders of magnitude. Following detailed simulations from Folding home of small cells known as vesiclesinthe Pande lab introduced a new computing method to measure the topology of its structural changes during fusion.
Mutations to hemagglutinin affect how well the protein binds to a host's cell surface receptor molecules, which determines how infective the virus strain is to the host organism. Knowledge of the effects of hemagglutinin mutations assists in the development of antiviral drugs. In MarchFolding home launched a program to assist researchers around the world who are working on finding a cure and learning more about the coronavirus pandemic.
The initial wave of projects simulate potentially druggable protein targets from SARS-CoV-2 virus, and the related SARS-CoV virus, about which there is significantly more data available. Drugs function by binding to specific locations on target molecules and causing some desired change, such as disabling a target or causing a conformational change.
Ideally, a drug should act very specifically, and bind only to its target without interfering with other biological functions. However, it is difficult to precisely determine where and how tightly two molecules will bind. Due to limits in computing power, current in silico methods usually must trade speed for accuracy ; e.
Folding home's computing performance allows researchers to use both methods, and evaluate their efficiency and reliability. This accuracy has implications to future protein structure prediction methods, including for intrinsically unstructured proteins, distributed computing thesis. Chemical activity occurs along a protein's active site. Traditional drug design methods involve tightly binding to this site and blocking its activity, distributed computing thesis, under the assumption that the target protein exists in one rigid structure.
Proteins contain allosteric sites which, when bound to by small molecules, can alter a protein's conformation and ultimately affect the protein's activity, distributed computing thesis. These sites are attractive drug targets, but locating them is very computationally costly, distributed computing thesis. Indistributed computing thesis, Folding home and MSMs were used to identify allosteric sites in three medically relevant proteins: beta-lactamase, interleukin-2and RNase H.
Approximately half of all known antibiotics interfere with the workings of a bacteria's ribosomea large and complex biochemical machine that performs protein biosynthesis by translating messenger RNA into proteins. Macrolide antibiotics clog the ribosome's exit tunnel, preventing synthesis of essential bacterial proteins. Inthe Pande lab received a grant to study and design new antibiotics. There are many more protein misfolding promoted diseases that can be benefited from Folding home to either discern the misfolded protein structure or the misfolding kinetics, and assist in drug design in the future.
The often fatal prion diseases is among the most significant. A prion PrP is a transmembrane cellular protein found widely in eukaryotic cells. In mammals, it is more abundant in the central nervous system. Although its function is unknown, its high conservation among species indicates an important role in the cellular function. The conformational change from the normal prion protein PrPc, stands for cellular to the disease causing isoform PrPSc stands for prototypical prion disease— scrapie causes a distributed computing thesis of diseases collectly known as transmissible spongiform encephalopathies TSEsincluding Bovine spongiform encephalopathy BSE distributed computing thesis bovine, Creutzfeldt-Jakob disease CJD and fatal insomnia in human, chronic wasting disease CWD in the deer family.
Distributed computing thesis conformational change is widely accepted as the result of protein misfolding. What distinguishes TSEs from other distributed computing thesis misfolding diseases is its transmissible nature.
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Thesis and Research Topics in Computer Science Completing a masters Thesis in computer science is the most challenging task faced by research scholars studying in universities all across the world. As computer science is one of the most vast fields opted by research scholars so finding a new thesis topic in computer science becomes more difficult 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. Folding@home is currently based at Washington University in St. Louis In distributed computing, a remote procedure call (RPC) is when a computer program causes a procedure to execute in a different address space (commonly on another computer on a shared network), which is coded as if it were a normal (local) procedure call, without the programmer explicitly coding the details for the remote interaction. That is, the programmer writes essentially the same code
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