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F@H Updates

Discussion in 'Folding@Home - Join Team Guru3D !' started by PantherX, Jun 1, 2010.

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From the Official FAH Blog:
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Src kinase: Project 10471
January 26, 2015 by Sonya Hanson ·

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.

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iancook221188, Jan 27, 2015

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iancook221188 Ancient Guru

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Cancer Systems Biology Scholars Program
January 28, 2015 by Vijay Pande ·

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.
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iancook221188, Jan 28, 2015

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iancook221188 Ancient Guru

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Huntington’s Disease Society of America SF Celebration of Hope
January 29, 2015 by Vijay Pande ·

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.

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iancook221188, Jan 31, 2015

#283
iancook221188 Ancient Guru

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Big Adv Program Ends January 31
January 31, 2015 by Vijay Pande ·

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.
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iancook221188, Jan 31, 2015

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iancook221188 Ancient Guru

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Video on the technical details of FAH
February 19, 2015 by Vijay Pande ·

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.
https://www.youtube.com/watch?v=CkeTGaUKYrA
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iancook221188, Feb 24, 2015

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iancook221188 Ancient Guru

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Modeling cyclic RGD peptides
February 24, 2015 by Vincent Voelz ·

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.

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iancook221188, Feb 25, 2015

#286
iancook221188 Ancient Guru

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Combining Markov state models and experiments to find new druggable sites
February 24, 2015 by Greg Bowman ·

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
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iancook221188, Feb 25, 2015

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iancook221188 Ancient Guru

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Updated psummary page
February 25, 2015 by Vijay Pande ·

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.
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iancook221188, Mar 1, 2015

#288
iancook221188 Ancient Guru

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Removal of the bonus for A4-core based projects starting March 2, 2015
February 27, 2015 by Vijay Pande ·

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
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iancook221188, Mar 1, 2015

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iancook221188 Ancient Guru

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Folding@Home client for Android Mobile phones
March 19, 2015 by Mark Piercy ·

We’re happy to announce that our Folding@Home client for Android Mobile phones has now entered the next stage of beta. This version is available to all Android Mobile phones with version 4.4 (Kitkat) and above. The version also contains an update of the mmlib.

Scientifically, as in our previous beta run, we continue to focus on the breast cancer with our mobile app. In this project, we are investigating the nature of drug resistance mutations in key proteins (kinases) that are targets for breast cancer drugs. By studying the nature of how these mutations change these key drug targets, we will be able to both advance our basic biophysical understanding of these key proteins as well as build a tool to be used for patient specific breast cancer treatment— by sequencing the tumor and seeing what mutations are present, our tool seeks to recommend the best drug for a specific patient.

We are planning user experience updates in the coming months, including updates in areas suggested by donors. We have been very excited about the donor reaction so far. The beta version has been downloaded more than 150,000 times worldwide, with more than 53,000 mobile phones contributing at the same time.
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iancook221188, Mar 22, 2015

#290
iancook221188 Ancient Guru

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Using MSMs to study the effect of tryptophan mutations on folding
May 1, 2015 by Vincent Voelz ·

In a new paper, we describe our efforts to use Markov State Models (MSMs) to study the how tryptophan mutations affect the folding and conformational dynamics of a series of model beta-hairpin peptides.

This work represents the most extensive explicit-solvent simulations of ***946;-hairpins to date (9.4 ms in aggregate), a feat made possible through the much-appreciated efforts of Folding@home contributors! The trajectory data obtained through Folding@home made possible the construction of high-resolution MSMs, where we used the same set of metastable conformational states for multiple sequences. Thus, we could ask how tryptophan mutations perturb the transitions between individual states, as well as the global folding kinetics and stability.

Our study predicts that sequences with tryptophans near the hairpin termini (a so-called beta-cap motif) fold much more cooperatively and are more stable than the “wild-type” sequence, consistent with experimental studies. Also consistent with experiment, we find that a sequence with four tryptophans (trpzip4) has slower folding kinetics than wild-type. Our models show that this is in part due to many non-native “traps” that slow down folding, consisting of many inverted topologies of the hairpin. The existence of these traps may help explain why tryptophan-rich proteins are rare in nature, despite their ability of tryptophan to stabilize folds. We believe that MSM-based studies like this one are a great tool for studying the relationship of sequence to structure and function, and we expect them to find increasing relevance toward protein design.
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iancook221188, May 3, 2015

#291
iancook221188 Ancient Guru

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NaCl client stats update
May 4, 2015 by Vijay Pande ·

Good news for NaCl donors: we’ve found an issue with one of the NaCl servers in Hong Kong that wasn’t awarding points (whereas the servers at Stanford have been), so we expect NaCl client donors to see some more points coming their way.
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iancook221188, May 8, 2015

#292
iancook221188 Ancient Guru

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New Maxwell WUs
May 5, 2015 by Vijay Pande ·

A heads up for GPU donors: We’ve been looking into issues with Maxwell GPU project WUs shortages. In addition to adding more WUs, we are also working to improve our monitoring tools. With so many different variants of WUs, it’s easy for a specific sub-subtype (GPU WUs are a subtype, Maxwell a sub-substype) to run out if they are in high demand.
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iancook221188, May 8, 2015

#293
iancook221188 Ancient Guru

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Fixes for recent FAH server outage
May 7, 2015 by Vijay Pande ·

We recently ran into some problems with our assignment server (AS). The AS is responsible for distributing the computational power of Folding@home by sending client’s to different work servers (WS), which in turn assign parts of the protein folding simulations to clients. In the interest of transparency, here’s what happened.

Two issues compounded to cause some clients to not get work assignments for many hours. The first problem is an issue we’ve run into before where the AS exceeds the number of open files allowed by the operating system. When this happens it continues to run but fails to assign. To address this problem, our lead developer (Joseph Coffland) has added code to the AS which will check the maximum allowed open files at startup and increase the limit to the highest possible value. If the value is still too low it will print a warning to the log file. This will help us ensure that our file limit settings are actually being respected.

The second issue was that failover to our second AS (assign2) didn’t work for some clients. This was related to how we handle clients that cannot connect to port 8080 and WS that cannot receive connections on port 80. The folding client will first attempt to connect to assign.stanford.edu on port 8080 if this fails it will try assign2.stanford.edu on port 80. The AS assumes that connections on port 80 are from clients which don’t support connections to 8080 and only assigns them to WS which support port 80.

In a failover situation, this assumption is invalid. The result is far fewer WS are available during a failover. To solve this problem the AS was modified to prefer rather than require WS which support port 80 for connections on port 80. This change can cause client/WS port mismatches but only when no better match was possible. Yes, it’s a tangled web.

In addition to these changes, we have plans to implement an early warning system which should help to alert us to such situations sooner. We already get SMS notifications if the AS goes down but we need more thorough reporting for situations where the AS is alive but not assigning. This new notification system will be put in place in the next few months.

Thank you for your patience and for your ongoing contributions to Folding@home!
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iancook221188, May 8, 2015

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Issue with fah-web.stanford.edu
May 17, 2015 by Vijay Pande ·

Likely due to a recent extremely heavy (and unusually rare) electrical storm, we’ve had some server issues last week. I thought we’d gotten them all but we see now that there’s an issue with fah-web.stanford.edu, which serves up both the Folding@home stats and project descriptions. While the stats are being accumulated on a separate server, fah-web is the web server that displays them to donors. I’ve taken a look at it and there’s a more serious issue with a particular server than I can take care of myself. I’ve filed a ticket with the sysadmin team. Best guess ETA on this being fixed is Monday at noon (assuming this is something simple).

The stats accounting is still going on and this appears to be just an issue with the web server (fah-web), so we expect that this resolution should be simple enough once our sysadmin team gets to this on Monday .
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iancook221188, May 18, 2015

#295
iancook221188 Ancient Guru

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Issue with fah-web.stanford.edu
May 17, 2015 by Vijay Pande ·

Likely due to a recent extremely heavy (and unusually rare) electrical storm, we’ve had some server issues last week. I thought we’d gotten them all but we see now that there’s an issue with fah-web.stanford.edu, which serves up both the Folding@home stats and project descriptions. While the stats are being accumulated on a separate server, fah-web is the web server that displays them to donors. I’ve taken a look at it and there’s a more serious issue with a particular server than I can take care of myself. I’ve filed a ticket with the sysadmin team. Best guess ETA on this being fixed is Monday at noon (assuming this is something simple).

The stats accounting is still going on and this appears to be just an issue with the web server (fah-web), so we expect that this resolution should be simple enough once our sysadmin team gets to this on Monday .

UPDATE Monday May 18 at 10am pacific time: We’ve got the machine back up and everything is looking good. It appears that the problem was the server was under heavy load post storm, leading to a PERQ reset under load, a longstanding issue, which causes filesystems fo go read-only or offline, with the start of the problem was May 16 19:21:52. We’re planning on buying new hardware to help here, especially since this hardware is on the older side now.
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iancook221188, May 25, 2015

#296
iancook221188 Ancient Guru

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Multi-core CPU jobs
May 21, 2015 by Vijay Pande ·

We’ve been getting reports that FAH is low on CPU jobs. We’re in the process of adding more multi-core jobs to existing projects.

Also, currently lead developer Joseph Coffland’s main project is to get a new Gromacs CPU core out to enable some new science on CPU cores (that’s currently only easily doable on GPU cores). We expect a rough ETA for the first testing of that new core to be in a few weeks.
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iancook221188, May 25, 2015

#297
iancook221188 Ancient Guru

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Introducing Shukla Group@Illinois
May 26, 2015 by Diwakar Shukla ·

Shukla group (http://www.shuklagroup.org) at University of Illinois at Urbana-Champaign has just configured new Folding@home servers (ds01[a-d].scs.illionis.edu), which would help us carry out exciting computational experiments in collaboration with the vibrant F@H community.

Before joining Illinois in January 2015, I was a post-doctoral fellow in Pande Lab, working on conformational change mechanism of proteins related to a variety of diseases including cancer, neurodegenerative & cardiovascular disorders. Some of the key results obtained using Folding@home resources on conformational change mechanisms of G-Protein Coupled Receptors and Kinases are highlighted in previous blog posts.

The mission of my group is to combine theory, computation, and experiments to develop quantitative models of biological phenomena relevant for health, energy and environmental challenges. These grand challenges would not only require new scientific methodologies and insights but also development of platforms that enable broader participation of the community of informed citizens in the pursuit of the solutions. Folding@home is one such unique platform that enables engagement with volunteers and donors to help us solve challenging scientific problems. Our group is excited to be a part of the Folding@home team and we look forward to working with all of you on projects related to key challenges in human health. Specific project details will be posted soon on folding forum and F@H blog.

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iancook221188, May 28, 2015

#298
iancook221188 Ancient Guru

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New Core tech update: OpenMM (GPU) and Gromacs (CPU)
May 29, 2015 by Vijay Pande ·

We’ve been pushing hard to improve the performance of OpenMM, especially in OpenCL as it’s now used in Folding@home. We’ve got some great news hot off of the presses. These are the benchmarks described at http://wiki.simtk.org/openmm/BenchmarkOpenMMDHFR. They’re using the very latest OpenMM code, what will be in OpenMM 6.3. They’re using CUDA 6.5 and running on Titan X. All numbers are in ns/day.
Benchmark Calculation CUDA OpenCL
Implicit, 2 fs 471 366
Implicit, 5 fs 684 589
Explicit-RF, 2 fs 305 265
Explicit-RF, 5 fs 508 460
Explicit-PME, 2 fs 161 164
Explicit-PME, 5 fs 318 354

We’re especially pleased with those OpenCL PME numbers. OpenMM Lead Developer Peter Eastman has put a lot of work into that for this release, and it now is actually faster than CUDA (For the Titan X). Curiously, that is not the case on GTX 980. It’s still slower than CUDA there, although it comes a lot closer than it used to.

This will be spun into an updated Folding@home core. The upshot for GPU donors is that PPD for that new core should increase, due to the expanded capabilities of the new code.

It’s important to stress that SMP/CPU donors aren’t left out of new performance (and therefore PPD) updates either: FAH Lead Developer Joseph Coffland has been working hard on a new Gromacs core and that should also see performance benefits, as we roll out AVX support for FAH.
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iancook221188, Jun 6, 2015

#299
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Problem with NaCl Client
June 6, 2015 by Vijay Pande ·

We see that there is an issue with our NaCl Client (at http://folding.stanford.edu/nacl), with donors seeing this error:

Warning: Unexpected response to AS assignment request: error,DB ERROR: IO error: log.leveldb/016519.ldb: Too many open files

The server is being overloaded and our sysadmin team will take a look at it when they get back on Monday. Long term, it looks like it’s time for us to upgrade the server this is running on since it’s getting overloaded. We have been moving to get new servers ready for this and so getting to that should happen in about a week (servers are here and the sysadmin team has been working to getting them ready for their new roles in FAH).
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iancook221188, Jun 8, 2015

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