Removal of the bonus for A4-core based projects starting March 2, 2015

The A4-core bonus was a 10% bonus started in mid 2012 as a temporary bonus to incentivize Folding@home donors to upgrade their clients to version 6.34 and above, allowing scientists using FAH to be able to research larger and more complex biological problems. This has been very successful allowing us to computationally investigate much larger systems including enzymes involved in cancers and vision (see recent blog posts and published work on the Src Kinase, protein kinase C, Rhodopsin, and many others).

While the A4 bonus was designed to be temporary, it has been in place for multiple years, considerably longer than its expected lifetime of three months. We believe it is now time to retire the A4 bonus. Therefore starting March 2, 2015, A4 core based projects will no longer receive both the 10% bonus and the quick return bonus.  (They will continue to receive the quick return bonus like most other projects.)

The change should be seamless but please be aware that starting March 2, 2015, returning A4-core work units will see an approximate 10% drop in credited points.

Updated psummary page

Our psummary, or project summary, is a Web page we publish which lists information about all currently active folding projects.  Last fall, we updated psummary to work with our new assignment server (AS).  Initially, we published the new psummary to a new URL and left the old psummary in place.

Since the old psummary does not contain information about some new projects, and the new psummary and AS have stabilized, we have decided it is finally time to deprecate the old psummary.  Next week we will replace the old psummary with the new.

This change may impact some third-party tools which parse the psummary HTML but we hope the developers of these tools will update their code soon.  To mitigate such problems in the future we now also publish the psummary data in JSON format. Third-party tools should use the JSON data instead of parsing the HTML, which may change from time to time.

Combining Markov state models and experiments to find new druggable sites

Rational drug design efforts typically focus on identifying inhibitors that bind to protein active sites. Pockets that are not present in crystallographic structures yet can exert allosteric (i.e., long-range) control over distant active sites present an exciting alternative. However, identifying these hidden allosteric sites is extremely challenging because one usually has to simultaneously find a small molecule that binds to and stabilizes the open conformation of the pocket. In our new PNAS paper, the Bowman lab presents a means of combining advances in computer modeling—using Folding@home and Markov state models to capture long timescale dynamics—with biophysical experiments to identify hidden allosteric sites without requiring the simultaneous discovery of drug-like compounds that bind them. Using this technology, we discover multiple hidden allosteric sites in a single protein.

Modeling cyclic RGD peptides

RGD peptides (those which contain a conserved Arg-Gly-Asp sequence) can adopt a hairpin loop structure found in integrin-binding proteins such as fibronectin, fibrinogen, and vitronectin. Over the last few decades, researchers have sought to develop cyclic RGD peptides that can bind potently to integrin, an important cancer target. The most successful of these to date, cilengitide (cyclo-RGDf-[N-Me]V), was discovered using a strategy of screening various chemical substitutions to find designs whose structures were more rigid. Cilengitide inhibits the binding of tumor cells to the extracellular matrix, which prevents vascularization and induces cell apoptosis. While cilengitide in particular has performed disappointingly in recent phase III clinical trials against glioblastoma, cyclic peptides in general are an exciting new platform for drug development.

In several projects soon to be released to Folding@home, we are trying to understand how to design rigid cyclic peptides in silico. First, we are have been quantifying just how accurate molecular simulations are at predicting the conformational properties of cyclic RGD peptides in solution. In a submitted manuscript, we report excellent agreement with previously published experimental data. Second, we are simulating the binding of cyclic RGD peptides to integrin to understand the relative contributions of conformational entropy (i.e. rigidity) and enthalpy (i.e. the strength of the intermolecular binding forces). Several previous studies have shown that achieving the right balance of these factors is tricky—a problem we hope our work can address.

cilengitide

Video on the technical details of FAH

Here’s a video on the more technical details of Folding@home:  how it works, what we’ve done, where we’re going, etc.  It’s a recording of a talk I presented at the NCSA at the University of Illinois in 2014.

Big Adv Program Ends January 31

As we have previously announced, the bigadv (BA) program will reach end-of-life on January 31, 2015.  We would like to thank all the donors who have contributed to the program.  Throughout the history of Folding@home, donor participation has enabled us to tackle hard problems and engage in bold experiments.  The BA program is an example of both of these––the projects in BA are one that simply could not have been addressed otherwise.  We are still analyzing the results of these projects, but the preliminary data already yields some exciting results that we are comparing to experiments.

Although the BA program is ending, we recognize that the many-core systems previously used to run BA may not perform optimally on all work units in the Folding@home ecosystem (although they will do quite well on most).  In an ideal world, we would have each project performance-benchmarked on a wide variety of systems and a dynamic allocation scheme that matches clients to projects that perform well on their hardware while ensuring a distribution of client capability across Folding@home scientific priorities.  However, this sort of matching is more technically involved (and places larger demands on the assignment server) than we are able to offer at this time.  At BA end-of-life, in order to make sure that these many-core get WUs best suited for them, clients continuing to use the BA flags will be directed to large work units, although these will carry the normal Folding@Home points scheme rather than a BA scheme.  We are planning to expand the diversity of these work units to include a variety of “large” simulation problems, but at this point we are not making statements as to the anticipated longevity of this scheme.

Thank you once again for contributing to Folding@home, whether the BA program or any of our other initiatives.  All our past and future scientific achievements are due to your participation and generosity.

Huntington’s Disease Society of America SF Celebration of Hope

HD-SF-2015On Saturday May 30th, 2015, the Huntington’s Disease Society of America SF Celebration of Hope will Honor Prof. Pande for his work with Folding@home.  Details are in poster to the right (click on it to enlarge it) and this link.

 

Cancer Systems Biology Scholars Program

I’m happy to announce our participation in the Cancer Systems Biology Scholars (CSBS) program, which provides a unique opportunity for postdoctoral training in cancer systems biology in a dynamic, multi-disciplinary environment.  A diverse group of mentors, all with independently funded research projects in cancer research, participate with expertise in many disciplines. CSBS trainees will conduct research, participate in specialized coursework and seminars, and attend a regular meeting of CSBS mentors and trainees, as part of an integrated, two-year program.

For those looking to be a postdoctoral fellow in the program, I encourage you to apply:

http://med.stanford.edu/csbs/apply/

This would be an opportunity to work on Cancer in the Pande Lab/Folding@home or with any of the other mentors associated with the CSBS at Stanford.  The application deadline is March 2, 2015. Priority will be given to applications received by March 2. Applications received after March 2 will be considered until positions are filled.

Src kinase: Project 10471

In Project 10471 we at the Chodera lab are looking at Src kinase. The Src gene was first discovered as responsible for the tumorogenicity of Rous sarcoma virus. This gene is also present in animals, and it is in fact a mutated Src gene that is injected back into the host that causes cancer, not a viral gene. The discovery that cancer was a result of mutated naturally occuring genes and not viral ones was a milestone in cancer research and Harold E. Varmus and J. Michael Bishop were awarded the Nobel Prize in Physiology or Medicine for this and related discoveries of the cellular origin of retroviral oncogenes in 1989.

Since then Src has been found to be over-expressed and/or highly activated in a variety of cancers, most notably linked to metastasis in breast, prostate, and colon cancers. The drug dasatinib of Bristol-Myers Squibb (Sprycel commercially), has been approved for treatment of CML (described more fully in our blog post on Abl kinase), but it was also recently in clinical trials for metastatic prostate cancer due to its affinity for Src kinase.

We are not only interested in Src kinase for its intrinsic value, but also to compare and contrast its behavior with Abl kinase in Project 10472. While dasatinib targets both Src and Abl kinase, only Abl and not Src is sensitive to the drug imatinib, despite the nearly identical imatinib bound poses seen in the Src and Abl crystal structures (pictured). Because these static structures are so similar, we are looking forward to using the long timescale simulations of these two kinases on Folding@home to help us understand their different small molecule binding properties.Src_Abl_IMA words

New psummary page

As part of our recent assignment server upgrades we are rolling out a new psummary page (which lists all of the active Folding@home projects).  This new page includes projects which are no longer visible in the old psummary system.  The new psummary uses a more modern HTML but is otherwise the same.

We have aimed to make psummary backwards compatible with 3rd party tools which parse this data.  However, there may be some inconsistencies depending on how these tools operate.  To help eliminate such problems in the future we have exposed psummary in JSON format via the AS here:

http://assign.stanford.edu/api/project/summary

http://assign2.stanford.edu/api/project/summary

 

The new psummary is here:

http://fah-web.stanford.edu/new/psummary.html

 

The previous HTML psummary will continue to be found here for a while:

http://fah-web.stanford.edu/psummary.html

Note , we plan to eventually deprecate the old psummary and therefore encourage 3rd party tool creators to update their software to use the new URL as soon as possible.

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