Rosetta@home project details

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Alez
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#1 Rosetta@home project details

Post by Alez »

Rosetta@Home

What is Rosetta@home?

Rosetta@home needs your help to determine the 3-dimensional shapes of proteins in research that may ultimately lead to finding cures for some major human diseases. By running the Rosetta program on your computer while you don't need it you will help us speed up and extend our research in ways we couldn't possibly attempt without your help. You will also be helping our efforts at designing new proteins to fight diseases such as HIV, Malaria, Cancer, and Alzheimer's (See our Disease Related Research for more information). Please join us in our efforts! Rosetta@home is not for profit.
Follow us on Twitter: @rosettaathome

We believe that we are getting closer to accurately predicting and designing protein structures and protein complexes, one of the holy grails of computational biology. But in order to prove this, we require an enormous amount of computing resources, an amount greater than the world's largest super computers. This is only achievable through a collective effort from volunteers like you.

For more information, click on the following links:

Welcome from David Baker
Quick guide to Rosetta and its graphics
Disease Related Research
Research Overview
David Baker Profile - Protein Folding (UW Cyberscience Symposium Article)
News & Articles about Rosetta
David Baker's Rosetta@home Journal
Publications


Why predict and design protein structures and complexes?

Proteins are the molecular machines and building blocks of life. Their functions and interactions are critical for the chemical and biological framework and processes of all living organisms. The function of a protein and how it iteracts with other molecules are largely determined by its shape (the three-dimensional structure). Proteins are initially synthesized as long chains of amino acids and, for the most part, they cannot function properly until they fold into intricate globular structures. Understanding and predicting the rules that govern this complex folding process -- involving the folding of the main backbone and the packing of the molecular side chains of the amino acids -- is one of the central problems of biology. Knowing how proteins fold and interact with other molecules and determining their functions may ultimately lead to drug discoveries and cures for human diseases. Currently, millions of dollars are being spent in structural genomics efforts to determine the structures of proteins experimentally using X-ray crystallography and nuclear magnetic resonance (NMR). If this could be done computationally, it would significantly reduce the cost and revolutionize structural biology. Designing protein structures and complexes also offers significant scientific and practical benefits. If one can design completely new structures, one can potentially design novel molecular machines -- proteins for carrying out new functions as therapeutics, catalysts, etc. And finally, there's the evolutionary question of whether the folds that are sampled in nature are the limit to what's possible; or whether there are quite different folds that are also possible. Understanding the rules that govern folding and design may help answer this question.

Please visit the following Wikipedia links for more general information about:

Proteins
Protein folding
Protein structure prediction
Protein design

Image docking Image design Image hires prediction Image prediction

How accurate are our predictions?

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CASP6 Target T281 Rosetta was shown repeatedly to be one of the best methods for predicting the three-dimensional structures of proteins in the Critical Assessment of Techniques for Protein Structure Prediction (CASP), and has also been successful in CAPRI, the Critical Assessment of Prediction of Interactions. A highlight of CASP6 was the first de novo blind prediction that used our high-resolution refinement methodology to achieve close to high-resolution accuracy. The relatively short sequence (76 residues) allowed us to apply our all-atom refinement methodology not only to the native sequence but also to the sequence of many homologs. The center of the lowest energy cluster of structures turned out to be remarkably close to the native structure (1.5 Å). The-high resolution refinement protocol decreased the RMSD from 2.2 Å to 1.5 Å, and the side chains pack in a somewhat native-like manner in the protein core. In CAPRI, predictors are given the structures of two proteins known to form a complex, and challenged to predict the structure of the complex. Our predictions for targets without significant backbone conformational changes were striking. Not only were the rigid-body orientations of the two partners predicted nearly perfectly but also almost all the interface side chains were modeled very accurately. Our design methods also have shown to produce accurate results. Particularly exciting recently is the creation of novel proteins with arbitrarily chosen three-dimensional structures. For example, our methods were used to design a 93-residue protein called TOP7 with a novel sequence and topology. TOP7 was found to be monomeric and folded, and the x-ray crystal structure of TOP7 is strikingly similar (RMSD of 1.2 Å) to the design model.

Plans for the future

Our methods will be tested in upcoming CASP and CAPRI experiments and implemented in our publicly available protein structure prediction server, Robetta, which is currently used by hundreds of academic scientists from around the world for free, and has been shown to be one of the best fully-automated structure prediction servers in recent CASP experiments. If there are enough Rosetta@home participants, we also plan to use Rosetta@home to provide computational resources that will reduce the long wait period for structure predictions on the Robetta server and will enable us to add more functionality, such as design and docking, that we currently cannot provide because of limited computing resources. By integrating Robetta and Rosetta@home, volunteers, like you, will not only help our efforts, but will directly help the efforts of scientists from around the world doing critical research on biomedical issues such as cancer, SARS, HIV/AIDS, malaria, and much more.

Feedback to participants

Wouldn't you, as a participant, like to know the results of the predictions made on your computer -- how accurate your best model was, how did it compare with others, what did it look like, who and how has it helped? We plan to provide such information on the Rosetta@home website and, when possible, link it to the predictions requested by scientists through the Robetta server. You can already keep track of the amount of computing work ("credits") that you have donated and compare it to others from our statistics page.

View Windows Media videos of Rosetta predictions

folding Ubiquitin (file size 4M),
re-packing side-chains of TOP7 (file size 2.4M),
and selecting optimal side-chain rotamers for TOP7 (design) (file size 4.7M).


Note: Windows Media Player is required. Videos were created by Jens Meiler.
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Alez
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#2 Re: Rosetta@home project details

Post by Alez »

Updated and revised details for the project
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Alez
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#3 Re: Rosetta@home project details

Post by Alez »

Rosetta@home Science FAQ

What is Rosetta?
Rosetta is a protein structure prediction and design program.

What is a protein?
A protein is a polymer of amino acids that is encoded by a gene.

What are amino acids?
Amino acids are chemical moieties that form the basic building blocks of proteins. There are 20 different amino acids that are specified by the genetic code. These 20 amino acids fall into different groups based on their chemical properties: acidic or alkaline, hydrophilic (water-loving) or hydrophobic (greasy).

What do proteins do?
Proteins perform many essential functions in the cells of living organisms. They replicate and maintain the genome (DNA), they help cells grow and divide, and stop them from growing too much, they give a cell its identity (eg liver, neuron, pancreatic, etc.), they help cells communicate with each other. Proteins, when mutated or when affected by toxins can also cause disease, such as cancer or alzheimer's. Bacterial and viral proteins can hijack a cell and kill it. In short, proteins do everything.

How do proteins perform all their different functions?
Each protein folds into a unique 3-dimensional shape, or structure. This structure specifies the function of the protein. For example, a protein that breaks down glucose so the cell can use the energy stored in the sugar, will have a shape that recognizes the glucose and binds to it (like a lock and key). It will have chemically reactive amino acids that will react with the glucose and break it down, to release the energy.

Why do proteins fold into unique structures?
It's long been recognized that most for most proteins the native state is at a thermodynamic minimum. In English, that means the unique shape of a protein is the most stable state it can adopt. Picture a ball in a funnel - the ball will always roll down to the bottom of the funnel, because that is the most stable state.

What forces determine the unique native (most stable) structure of a protein?
The sequence of amino acids is sufficient to determine the native state of a protein. By virtue of their different chemical properties, some amino acids are attracted to each other (for example, oppositely charged amino acids) and so will associate; other amino acids will try to avoid water (because they are greasy) and so will drive the protein into a compact shape that excludes water from contacting most of the amino acids that "hide" in the core of this compacted protein.

Why is it so difficult to determine the native structure of a protein?
Even small proteins can consist of 100 amino acids. The number of potential conformations available to even such a (relatively) small protein is astronomical, because there are so many degrees of freedom. To calculate the energy of every possible state (so we can figure out which state is the most stable) is a computationally intractable problem. The problem grows exponentially with the size of a protein. Some human proteins can be huge (1000 amino acids).

So how does Rosetta approach this problem?
The rosetta philosophy is to use both an understanding of the physical chemical properties different types of amino acid interactions, and a knowledge of what local conformations are probable for short stretches of amino acids within a protein to adopt, to limit the search space, and to evaluate the energy of different possible conformations. By sampling enough conformations, Rosetta can find the lowest energy, most stable native structure of a protein.

Why is distributed computing required for structure prediction by Rosetta?
In many cases where the native structure of a protein is already known, we have noticed that Rosetta's energy function can recognize the native state as more stable than any other sampled state. When starting from a random conformation, however, we've observed that the native state is never sampled. By applying more computing power to the problem, we can sample many more conformations, and try different search strategies to see which is the most effective.

How will Rosetta@home benefit medical science?
Please see our Disease Related Research page for information on how Rosetta is being applied to medical problems.
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