Folding@home Diseases Studied FAQ

Table of Contents

Introduction

The Folding@home project (FAH) is dedicated to understanding protein folding, the diseases that result from protein misfolding and aggregation, and novel computational ways to develop new drugs in general. Here, we briefly describe our goals, what we are doing, and some highlights so far.

We feel strongly that a Distributed Computing project must not just run calculations on millions of PC's, but DC projects must produce results, especially in the form of peer reviewed publications, public lectures, and other ways to disseminate the results from FAH to the greater scientific community. Below, we also detail our progress in these areas as well.

Most updates are announced in the main Folding@home blog, but we will periodically update this page. For the latest news, please see the blog.

What is protein folding and how is it related to disease?

Proteins are necklaces of amino acids, long chain molecules.

Proteins are the basis of how biology gets things done. As enzymes, they are the driving force behind all of the biochemical reactions that 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. 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 sequence tells us little about what the protein does and how it does it. In order to carry out their function (e.g. 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."

What happens if proteins don't fold correctly?

Diseases such as Alzheimer's disease, Huntington'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.

Which diseases or biomedical problems are you currently studying?

Alzheimer's Disease (AD)

AD is caused by the aggregation of relatively small (42 amino acid) proteins, called Abeta peptides. These proteins form aggregates which even in small clumps appear to be toxic to neurons and cause neuronal cell death involved in Alzheimer's Disease and the horrible neurodegenerative consequences.

We have many calculations being performed on AD. Our primary goals are the prediction of AD aggregate structure for rational drug design approaches as well as further insight into how AD aggregates form kinetically (hopefully paving the way for a method to stop the AD aggregate formation).

There have been many projects, including 500 series and 700 series. So far, all of them are either Tinker WUs or normal (not bigWU) Gromacs WUs.

2005

• We are currently in the process of submitting our first paper on FAH results.
• FAH researchers Vishal Vaidyanathan and Nick Kelley present the recent FAH results on AD at BCATS 2005. Their work won the best talk award in 2005.
• Prof. Vijay Pande presented recent FAH work on AD at the National Parkinson's Foundation conference (in the session on AD and its connections to PD).

2006

• Our first paper on AD is ready to submit. We hope to start publicly talking about these results very soon.
• We have submitted our first paper for peer review and we're working on the next 2 paper right now. We're very excited about the results!

2007 We have made some significant progress experimentally testing our computational predictions using NMR.

2008 The first of the papers has come out (see paper #58 on our Results page: "Simulating oligomerization at experimental concentrations and long timescales: A Markov state model approach").

2009 We have had some exciting results regarding new possible drug leads for Alzheimer's. We hope to be submitting these soon for publication.

2010 We have been working closely with the Nanomedicine Center for Protein Folding on pushing our lead compounds forward. They have gone from the test tube to the first round of testing beyond that (onto tissue) and we're continuing to refine the compounds based on the results obtained so far. Also, FAH researcher Dr. Yu-Shan Lin has been awarded a BioX Postdoctoral Fellowship for her proposed work on Alzheimer's Disease simulation.

Huntington's Disease (HD)

HD is caused by the aggregation of a different type of proteins. Some proteins have a repeat of a single amino acid (glutamine, often abbreviated as "Q"). These poly-Q repeats, if long enough, form aggregates which cause HD. We are studying the structure of poly-Q aggregates as well as predicting the pathway by which they form. Similar to AD, these HD studies, if successful, would be useful for rational drug design approaches as well as further insight into how HD aggregates form kinetically (hopefully paving the way for a method to stop the HD aggregate formation).

2006 We are currently in the process of submitting our first paper on FAH results.

2007 Nick has been working on a new collaboration with Judith Frydman's group to computationally test a new hypothesis for HD aggregation found in the Frydman lab.

2008

• Prof. Pande has presented the results on HD at a variety of Stanford internal conferences and meetings. People have been excited and interested in the results.
• We have also started to apply the drug design methods used in Alzheimer's to HD.

2009 New paper #62: The predicted structure of the headpiece of the Huntington protein and its implications for Huntington's Disease. It's still early (since this paper was just accepted), but I wanted to give FAH donors a heads up on our work on Huntington's Disease aggregation, which is just about to come out in the Journal of Molecular Biology.

2010 FAH research Dr. Veena Thomas has proposed a novel therapeutic strategy for HD and this proposal looks to be funded by NIH (as of September 22, 2010 still pending). This strategy is particularly exciting since it could be a quick way to bring the results from computation directly to a therapeutic.

Cancer and P53

Half of all known cancers involve some mutation in p53, the so-called guardian of the cell. P53 is a tumor suppressor which signals for cell death if their DNA gets damaged. If these cells didn't die, their damaged DNA would lead to the strange and unusual growths found in cancer tumors and this growth would continue unchecked, until death. When p53 breaks down and does not fold correctly (or even perhaps if it doesn't fold quickly enough), then DNA damage goes unchecked and one can get cancer. We have been studying specific domains of p53 in order to predict mutations relevant in cancer and to study known cancer related mutants.

2005

• Our first work on cancer has recently been published.
• We are expanding FAH's p53 work to other related p53 systems
• We are getting some interesting results from recent new FAH p53 projects.
• Two new sets of projects have completed and two new papers are being readied for peer-reviewed publication.

2006 FAH researcher Dr. Lillian Chong presented her work on p53 at a lecture at several US Universities.

2007 Plans have started to take a new approach for using FAH to fight cancer: to develop novel chaperonin inhibitors. FAH researcher Del Lucent is taking the lead.

2008 Del has presented his plans to the NIH Nanomedicine center with a very positive response. Planning for the lab side of this work has begun.

2009 Del has been involved in the development of new software methods (Ocker) for the chaperonin inhibitor project.

2010 In collaboration with the Nanomedicine Center for Protein Folding, we have been using our methods to further push a chaperonin inhibitor. This next round will use new scoring functions from Andrej Sali's lab at UCSF to push further what we could do in this area.

Chagas Disease

In 2010, we have started a pilot project on Chagas Disease, a major disease in Latin America. 2010 FAH/Pande Group researcher Paul Novick has applied ligand-based methods to Chagas disease and in collaboration with the SPARK project (UCSF) and the McKerrow Lab (UCSF) has started to test the results. The early results are looking promising, but it is very early to tell.

Malaria

In 2010, we have started a pilot project on Malaria. 2010 FAH/Pande Group researcher Dr. Veena Thomas has been building off methods used by PG member Paul Novick for Chagas to Malaria. This is very early stages, but with promising results from our Chagas disease work, this is a reasonable extension of that approach and of course could have a major impact on millions of people in the developing world.

Osteogenesis Imperfecta (OI)

In collaboration with other groups at Stanford (especially Dr. Teri Klein's group at Stanford University Medical Center), we are looking at Collagen folding and misfolding. Collagen is the most common protein in the body and mutations in collagen leads to a very nasty disease called Osteogenesis Imperfecta (or OI for short). In many cases, OI is lethal and leads to miscarriage. However, 1 in 10,000 people have some sort of mutational in collagen. For many, where the mutation is not very serious, it lies unknown and misdiagnosed and leads to brittle bones and other more subtle problems. In others, however, mutations lead to more serious morphological disorders (as shown on the right).

We are starting to model collagen folding and misfolding in the 1000 series projects. Follow the link for more information.

2005 FAH's first work on collagen has been accepted for publication

2006 FAH researcher Dr. Sangyhun Park presents his work on collagen at a lecture at Duke University

2007 Our paper on collagen folding has been accepted for publication.

2008 Our paper on collagen folding has come out.

For now, our Osteogenesis imperfecta stands still as a pilot project, with the bulk of our efforts going into AD and HD.

Antibiotics

The Ribosome is an amazing molecular machine and plays a critical role in biology, as it is the machine that synthesizes proteins. Because of this critical role, and some small but fundamental differences in the ribosomes of mammals and bacteria, the ribosome is the target for about half of all known antibiotics. These antibiotics typically work by preventing bacterial ribosomes from making new proteins, thus killing them. We have several projects on going to study the ribosome. Since the ribosome is so huge, these WUs are big WUs and have required us to push the state of the art of FAH calculations. However, with these new bigWUs, FAH is set up to study more and more complex problems, and if successful, with greater and greater biomedical impact.

2005

• We are working on our first paper resulting from FAH's ribosome simulations.
• Prof. Pande presents ribosome results at a protein folding conference at U Penn.
• Prof. Pande presents ribosome results at a lecture at University of California at San Francisco (UCSF) Medical School.
• Prof. Pande presents ribosome results at a lecture at Rice University.

2006

• Prof. Pande presents ribosome result at the NIH Roadmap center on Nanomedicine.
• We are just about to submit our first paper on the ribosome.
• Our first work units for antibiotic drug design calculations are now running on Folding@home.

2007 We have received a grant from Stanford University to design and study novel antibiotics. This is a joint grant with the labs of Chaitan Khosla at Stanford's Chemistry Department (who does small molecule synthesis, design, and some characterization) and Jody Puglisi at the Stanford Medical School (who studies the ribosome and antibiotics experimentally)

2008 Our first ribosome paper has come out in PNAS. See paper #59. Side-chain recognition and gating in the ribosome exit tunnel.

2009 Our second paper on the ribosome has been submitted for publication.

Parkinson's Disease (PD)

We have also performed preliminary studies on a key protein implicated in Parkinson's disease. Alpha-synuclein is a natively unfolded protein and its folding/misfolding (see figure on the right for misfolded aggregates) appears to be critically linked to PD. We are evaluating the application of various FAH methods to this problem.

2005

• We have only done a pilot study on PD and are looking for funding to continue our work in this area.
• Prof. Vijay Pande presented recent FAH work on AD at the National Parkinson's Foundation conference (in the session on AD and its connections to PD).

For now, PD stands still as a pilot project, with the bulk of our efforts going into AD and HD.

Viral diseases

Viruses such as influenza and HIV pose major threats to human health and can be exceptionally difficult to treat. Most treatments concentrate on preventing viral replication, but another strategy is to keep the virus out in the first place.

In order to infect human cells, viruses must pass through the cell membrane. They have established special machinery to accomplish this process, which usually requires an activation signal, a protein conformational change, and then protein-membrane interactions to achieve cell entry. Prof. Kasson's group studies this process to better understand and prevent viral diseases. We have focused on influenza both because it has a repeated history of causing widespread global disease (such as in 1918) and because advances in influenza treatment should be applicable to other similar viruses. Based on advances Dr. Kasson made while at Stanford in collaboration with Dr. Pande, we have made good initial progress in understanding the basic reactions influenza employs to enter cells. We are now well positioned to start studying the details of how the virus works. More information is available here.

How are these advances possible?

In order to make breakthroughs using distributed computing, new methods are critical. Distributed computing is an unusual way to perform large-scale calculations. While it gives computer resources much greater than a typical supercomputer (e.g. the almost 200,000 actively processing CPUs in FAH vs. 5,000 in a typical supercomputer), these processors are connected by the Internet, not the high speed, low latency interconnects found in supercomputers. Thus, we must develop new methods to use FAH's unusual computational paradigm and capabilities. Moreover, these methods must be tested.

Much of our work in the first years of FAH has been to develop and test these methods on model systems: small proteins that can be easily studied experimentally. With these experimental comparisons, we can test and validate our methods, as well as find out their limitations (which is critical for improving our methods).

To date, FAH has been very successful, with over 95 published works (as of August 2011) directly stemming from FAH calculations. We will continue to work on all fronts: new scientific cores, new server side algorithms, new models for proteins, and new questions related to testing our methods and applications to disease and other biomedical questions.

For More Information, Please See:

• Streaming video of talks given by Prof. Pande at PARC and Stanford
• Published Papers by the Folding@home Project
• FAH FAQ
• Folding Support Forum

Last Updated on November 27, 2011, at 06:56 AM