Proteins are the elementary machines inside every cell that we rely on to keep us alive and healthy. They assemble themselves by “folding.” When proteins misfold, there can be serious health consequences. If we better understand protein misfolding we can design drugs and therapies to combat these illnesses.
Why do proteins “fold”?
Protein folding and disease: BSE (Mad Cow), Alzheimer’s, Huntington’s, …
Why is protein folding so difficult to understand?
Why don’t you care about just the final structure?
Our solution: Use new distributed computing algorithms to simulate what wouldn’t be possible before
What have we done so far and where are we going?
How can I learn more about how Folding@home works and what it has done so far?
Could you tell me where to find more about the math behind Folding@home, i.e. the specific types of calculations being performed?
Proteins are necklaces of amino acids — long chain molecules. They come in many different shapes and sizes, and they are the basis of how biology gets things done. As enzymes, they are the driving force behind all of the biochemical reactions which make biology work. As structural elements, they are the main constituent of our bones, muscles, hair, skin and blood vessels. As antibodies, they recognize invading elements and allow the immune system to get rid of the unwanted invaders. They also help move muscles and process the signals from the sensory system. For these reasons, scientists have sequenced the human genome — the blueprint for all of the proteins in biology — but how can we understand what these proteins do and how they work?
However, only knowing this amino acid sequence tells us little about what the protein does and how it does it. In order to carry out their function (eg as enzymes or antibodies), they must take on a particular shape, also known as a “fold.” Thus, proteins are truly amazing machines: before they do their work, they assemble themselves! This self-assembly is called “folding.” Out of an astronomical number of possible ways to fold, a protein can pick one in microseconds to milliseconds (i.e. in a millionth to a thousandth of a second). How a protein does this is an intriguing mystery. One of our project goals is to simulate protein folding in order to understand how proteins fold so quickly and reliably, and to learn about what happens when this process goes awry (when proteins misfold).
What happens if proteins don’t fold correctly? Diseases such as Alzheimer’s disease, cystic fibrosis, BSE (Mad Cow disease), an inherited form of emphysema, and even many cancers are believed to result from protein misfolding. When proteins misfold, they can clump together (“aggregate”). These clumps can often gather in the brain, where they are believed to cause the symptoms of Mad Cow or Alzheimer’s disease.
Folding is a very complex process, and it’s often challenging to study in the laboratory. It’s amazing that not only do proteins self-assemble — fold — but they do so amazingly quickly: some as fast as a millionth of a second. While this time is very fast on a person’s timescale, it’s remarkably long for computers to simulate. In fact, even modern computers can take a day to simulate about 50 nanoseconds (50/1,000,000,000 of a second). Unfortunately, many proteins fold on the millisecond timescale (1,000,000 nanoseconds). Thus, it would take 20,000 days to simulate folding — i.e. it would take 60 years! That’s a long time to wait for one result!
Some research groups are interested in structure prediction, i.e. what is the final folded structure of a protein but not how it got there. In the cases of protein misfolding diseases, it is believed that the final structure is not the disease relevant state, but instead intermediate steps along the way cause the toxicity found in the disease. Thus, it is the path which is critically important to these diseases, not just the final structure.
Our group has developed multiple new ways to simulate protein folding which can break the fundamental barrier of simulating experimental timescales by dividing the work between multiple processors in a new way — with a near linear speedup in the number of processors. Thus, with power of Folding@home (approximately 500,000 processor-cores), we have successfully smashed the millisecond barrier and helped to unlock the mystery of how proteins fold.
Folding@home has been a success. In 2000-2001, we folded several small and fast folding proteins with experimental validation of our method. We are now working to further develop our method, and to apply it to more complex and interesting proteins and protein folding and misfolding questions. Since then (2002-2006), Folding@home has studied more complex proteins, reporting on the folding of many proteins on the microsecond timescale, including BBA5, the villin headpiece, Trp Cage, among others. In 2007, we crossed the millisecond milestone by simulating a protein called NTL9, and the 10 millisecond barrier in 2010 with ACBP.
More recently (2006-present), we have been putting a great deal of effort into studying proteins relevant for diseases, such as Alzheimer’s and Hunntington’s Disease. You can learn more about our results and peer-reviewed scientific achievements on our Papers Page.
A good place to start to learn about some of our success with Folding@home as well as how the project works is with some of our recent papers or recent press accounts of our work. Also, please check out our FAQ and in particular, our page on the diseases and biomedical questions we are studying. There is additional information on the FAH News Blog and the Folding@home article on Wikipedia.