Recent work from Folding@home highlighted in Biophysical Journal

Our recent work on understanding how protein misfolding occurs (http://www.cell.com/biophysj/abstract/S0006-3495(14)00722-X) has shed light on the nature of misfolding and potential subsequent aggregation (relevant for protein misfolding disease), demonstrating that misfolded states are more prevalent than would be expected, especially due to their metastability (once you get into a misfolded state, it’s really hard to get out of it).

The work was also recently highlighted in a separate article in the Journal (http://www.cell.com/biophysj/abstract/S0006-3495(14)00723-1 ).

New results for “Opa proteins”

We’re excited to share some recent results from our lab that combine simulation and experimental structural biology.  This has been a wonderful collaboration with my colleague Linda Columbus, a Chemistry professor at the University of Virginia.  We are interested in how Neisseria bacteria recognize and infect cells.  This is an important problem #1 because Neisseria are becoming increasingly drug-resistance and #2 because these mechanisms can be borrowed for targeted drug delivery.  Neisseria use a set of proteins called “Opa proteins” on their surface to bind to cells and get inside.  The structure of these proteins is very interesting–the part that sits in the membrane is well-structured, but the part that actually performs recognition is very flexible.  When Prof. Columbus started studying these using NMR spectroscopy (a way to determine molecular structure), the data she got on the recognition end of the protein wasn’t enough to uniquely determine the structure.  My lab and hers partnered to perform molecular simulations of Opa proteins–the recognition part of the protein is indeed flexible, but we were able to use molecular simulation and NMR together to define a bit better how the flexibility works and how it might be related to Opa’s function.  Part of why Opa is so flexible is that it must on the one hand bind to cell receptors but on the other vary enough to evade the human immune response.  We have a theory for what the Opa-cell receptor recognition complex might look like, and we are together performing more simulations and experiments to test this.

 

The work was published this summer in the Journal of the American Chemical Society:  http://pubs.acs.org/doi/abs/10.1021/ja503093y

Stanford’s Chemistry Department Research Highlights

Recently, for the first time, Stanford’s Chemistry Department did a look back at research highlights from the last (2013-2014) academic year done in the Department.  Folding@home is prominently highlighted:

https://chemistry.stanford.edu/events/chemistry-year-review

Stats update back on line

Over the weekend, we had an issue with one our key servers that handles the stats update.  The sysadmins have taken care of it and the stats update is now back on line.

Folding at the Chrome Browsers to Reveal the Secrets Behind the Type II Diabetes

In the past couple of years, Xuhui Huang’s group at HKUST
(http://compbio.ust.hk/) has performed large-scale molecular dynamics
simulations at Folding@Home (Project 2974-2975) to investigate the
mis-folding of the hIAPP (human islet amyloid polypeptide, also called
amylin).

Like other misfolding peptides, hIAPP is generally unstructured in
water solution but adopts an alpha-helix structure when binds to the
cellular membrane. Around 95% of patients with Type II diabetes
exhibit large deposits of misfolded hIAPP (beta-sheet fibrils).  The
aggregation of this peptide is suggested to induce apoptotic
cell-death in insulin-producing β-cells that may further cause the
development of the type II diabetes.  Using Markov state models
constructed from many molecular dynamics simulations, we have
identified the metastable conformational states of the hIAPP monomer
and the dynamics of transitioning between them.  We show that even
though the overall structure of the hIAPP peptide lacks a dominant
folded structure, there exist a large number of reasonably populated
metastable conformational states.  Among them, a few states containing
substantial amounts of β-hairpin secondary structure and extended
hydrophobic surfaces may further induce the nucleation of hIAPP
aggregation and eventually form the fibrils.  These results were
published at Qin, Bowman, and Huang,  J. Am. Chem. Soc., 135 (43),
16092–16101, (2013) (http://pubs.acs.org/doi/full/10.1021/ja403147m).

In 2014, our lab in collaboration with the Pande group at Stanford
University has successfully developed a new Folding@home client that
can run at the Chrome Web Browsers.  This new core is implemented on
Google Chrome’s Native Client (NaCl) platform (details here:
https://folding.stanford.edu/home/adding-a-completely-new-way-to-fold-directly-in-the-browser/).
Currently we have set up a NaCl folding server at Hong Kong
(folding5.ust.hk) to continue our study on the aggregation of the
hIAPP peptides.  Up to now, folding5.ust.hk has collected a few TBs
molecular dynamics simulation data of the hIAPP peptides.

We would like to thank all the donors for their generous
contributions!  We also welcome more clients to try out the new NaCl
Folding@home core.  If you are interested in this new core, you can
download it from the Chrome Store
(https://chrome.google.com/webstore/detail/foldinghome/hmnbjdgjgikbkapaolimfoidihobnofo).

 

Bowman lab moves to Washington University

I’ve been an independent researcher at UC Berkeley for the past three years and have now accepted an Assistant Professorship at Washington University in St Louis.  I’ll start the process of building a research team and our computing resources in the next few weeks, so I look forward to starting lots of new projects in the coming academic year!

Folding@home Next Steps Webinar Q&A

Last month Professor Pande gave a webinar/Q&A covering Folding@home’s next steps and accomplishments. Click on the link below to listen to and view the presentation-

http://on-demand.gputechconf.com/gtc/2014/webinar/gtc-express-folding-at-home-webinar.mp4

Bowman lab begins new vision projects

The Bowman lab is beginning a new effort to understand the molecular mechanisms underlying vision and the origins of inherited forms of blindness.  As a starting point, we’ve launched some new projects to understand the dynamics of rhodopsin. Rhodopsin is the protein responsible for detecting light in the eye and triggering a signaling cascade that ultimately results in an electrical stimulus that we perceive as an image. Rhodopsin functions by undergoing a conformational change in response to light. Importantly, mutations to rhodopsin can prevent it from having the desired dynamics, resulting in blindness. These projects will allow us to study the dynamics of rhodopsin, set a baseline for understanding the negative effects of such mutations, and potentially yield insight into therapeutic strategies for restoring or preventing vision loss.

Prof. Pande’s update on drug design successes with Folding@home

In the Stanford Big Data conference in 2014, I gave a talk which gives an update on our drug design efforts, summarizing a bit on how FAH works to design drugs and were we are in some areas (but not all — alas, it’s only a 12 minute talk, so I had to be pretty brief).  The talk is on the Stanford Big Data meeting web page:

http://bigdata.stanford.edu/advancing-drug-design-vijay-pande/

Folding@chrome – folding with just your browser

As those familiar with Folding@home (FAH) know, we’ve developed FAH to help simulate protein folding so that we can better understand how proteins get misfolded and cause diseases like Alzheimer’s, Mad Cow, Huntington’s, Parkinson’s, and many cancers. Better understanding protein misfolding allows designing drugs and therapies to combat these illnesses.

We have been working on ways to push FAH forward and have recently used a new technology provided by Google called Portable Native Client (PNaCl) to bring this folding application to the Web (via the Chrome browser ), so more people can contribute their computing power to solving this key problem.

For those interested in the technical details, Portable Native Client takes high-performance native code that uses a device’s full hardware capabilities and runs it in a browser tab, SIMD and threads included. PNaCl brings applications that need that extra computing power to the Web, and allows applications initially written for desktop (in C/C++ and making use of system interfaces like POSIX) to run in a browser. This is done portably, with support for x86-32, x86-64, ARM and MIPS on Windows, ChromeOS, Mac OS X and Linux.

In addition to making it easy for people to run Folding@home by simply going to this web page (with a Chrome browser), PNaCl also allows people to help FAH by embedding FAH+PNaCl into their own web pages, which would even further contribute computer power.   Our github page has instructions for how to do this.  Moreover, this NaCl client code is released with an open source license on github.

Folding@Home is supported by the NIH and NSF, and already has over 200,000 active users. It has been published in over 100 papers, including work in the prestigious journals Science and Nature. Please join us in finding the cure for these diseases, one laptop at a time, now with PNaCl support at http://folding.stanford.edu/nacl/

Add your computer's power to over 327,000 others that are helping us find cures to Alzheimer's, Huntington's, Parkinson's and many cancers ...

... in just 5 minutes.

Step 1.

Download protein folding simulation software called

Folding@home

.

Step 2.

Run the installation. The software will automatically start up and open a web browser with your control panel.

Step 3.

Follow the instructions to Start Folding.

Stanford University

will send your computer a folding problem to solve. When your first job is completed, your computer will swap the results for a new job.

Download the protein folding simulation software that fits your machine.

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Installation guide