In our simulations, we use models (aka “force fields”) of how a protein’s atoms interact physically. Recently, we’ve made an important advance in how to make these models, which will, in time, have a huge positive impact on Folding@home’s ability to make even more accurate predictions.
Our paper “Activation pathway of Src kinase reveals intermediate states as targets for drug design” in Nature Communications has just come out. As with Nature journals, it’s unfortunately behind a pay wall, but per NIH rules, it will become open access in a year. The key results in this paper is the use of FAH simulations to understand a key protein target in cancer (src kinase), especially to find new ways to target it for novel drug design.
A more technical summary is given in our abstract:
Unregulated activation of Src kinases leads to aberrant signaling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of large-scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In principle, the nature of conformational transition could be modeled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.
The Biophysical Society, an international group that brings together researchers taking a physical perspective on biology, just had its annual meeting in San Francisco. A number of us involved with Folding@home gave talks and/or posters and there was tremendous interest in what we’re doing. So, thanks to all of you for your help in facilitating great science!
Through a collaboration with Google, the Huang lab at UST Hong Kong, and the Pande Lab at Stanford University, we’ve been working on a new way to run Folding@home –– through the browser. The primary goal here is to make folding much easier to run, especially for non-expert computer users.
Open beta. We are happy to announce that we now ready to release a first open beta test of the web client. It uses Google’s Native Client (aka NaCl) technology, allowing one to run Folding@home in a browser.
If you’re curious to check it out, you can go to the FAH Chrome Store link. Note that this only runs in Chrome (minimum version 31). For support questions, we have created a new subforum at foldingforum.org.
Requirements. In order to use the Folding App, you need to cover these three basic requirements:
1) Use the Chrome Browser (Details) in Windows, Linux, or MacOS-X
2) Install the Folding App from the Chrome Web Store (Details)
3) Launch the Folding App and you are now folding!
Please note that there are some additional options which you can use to enhance your Folding experience:
1) You may configure the Folding App with a username (Details), Team number (Details) and a passkey (Details) though none of these are required. Please note that passkey is needed if you want to earn additional points for successfully finishing the Work Unit (WU) quickly.
2) If you don’t want to install the Folding App, you can always use the direct link in any Chrome Browser installed on Windows, Linux and OSX (Details).
Open source. This is the first F@H Client that is fully open sourced. The F@H Native Client (NaCl) uses a new Assignment Server (AS) and a new version of the Work Server (WS) which exposes a JSON interface with additional security for third party developers. The folding is done on a Gromacs (version 4.6.5) based FahCore which is closed-source for security reasons. Third party developers are encouraged to participate in the development (Details) and users can also keep track of open issues (Details). Developers can view the log file generated from NaCl by choosing the console view from the DevTools Window.
Next steps. Finally, as many will probably notice, this opens the door to naturally moving Folding@home from the browser on a computer to a browser on a phone or tablet. We are actively investigating those possibilities.
Some links to additional related material:
I’ll be presenting a webinar on Folding@home open to the public on Tuesday, May 27, 2014 9:00 AM – 10:00 AM PDT. You can register on this link: https://www2.gotomeeting.com/register/688201986. The goals are to talk about what we’ve been able to do so far and where we’re going.
Summary. Folding@home is a large-scale volunteer distributed computing project, started in October 1, 2000. For over a decade, new types of hardware (such as GPUs, multi-core CPUs, and PS3) and algorithms have been pioneered in order to make significant advances in our ability to simulate diseases at the molecular scale. Join Professor Vijay Pande from Stanford University for a brief introduction to the goals of Folding@home, followed by the successes so far. Prof. Pande will end with a discussion of what’s being done today, as well as the plans for greatly enhancing what Folding@home can do through new initiatives currently under way.
Please note that this webinar starts at 9:00 AM Pacific, 12:00 PM Eastern, and 5:00 PM BST.
We’ve been suspicious that the stats system has been undercounting ATI/AMD GPUs for some time now and we have found the issue. We’ve rolled out an update to the stats code and so we expect to see more ATI GPUs showing up in osstats.
I recently gave a webinar on OpenMM, the heart of our Core17 for GPUs (and also now more recently, high performance computing on multi-core CPUs as well). Here’s a link if you’re curious to learn more:
Our recent work on simulating kinases on Folding@home and the simulation’s use in identifying potential new cancer drug targets has been just accepted for publication in Nature Communications this morning. I’ll post more in the coming weeks with more details after the paper is past Nature’s embargo period.
We’ve added a few papers to the Papers page. The most important application result is our work on GPCR intermediates as new possible drug targets. We also have several new methodological advances which are proving important for our work going on right now.
Coming up (hopefully) soon will be a paper on new drug targets involving kinases, key protein targets involved in fighting cancer.
I’ll be speaking at the NVIDIA GTC on our recent work in cancer. Specifically, it’s talk S4133, entitled “OpenMM Molecular Dynamics on Kinases: Key Cancer Drug Targets Revealed with New Methods and GPU Clusters” and it is scheduled for 50 minutes on Tuesday, 3/25/2014 at 2:30:00 PM in Room LL21E.