We (the Bowman lab) have completed our move to Washington University in St Louis and have our new servers up and running. While our primary server won’t be replacing Folding@home anytime soon, with its 12 cores running at 2.1 GHz, its 64 TB of hard drive space will provide plenty of storage for new projects. Currently, we’re running a number of projects to understand how rhodopsin detects light and transforms this trigger into an electrical signal that we ultimately perceive as an image.
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 ).
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
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:
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.
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
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:
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
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!
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-
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.
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: