Vijay Pande's group at Stanford has become well-known for using the collective force of millions of CPUs around the world for simulating protein folding in the project known as Folding@home. One of the enduring challenges in simulating folding has been to sample the long timescales that are common in real-life folding events, and recent breakthroughs have made accessing such time domains realistic. We should expect long protein folding simulations to be within the reach of many non-specialists in the next few years.
In the latest issue of JACS, Pande's group provides an example of such advances by simulating the folding of a 39 residue protein called NTL9. The actual folding time is 1.5 ms so this is a substantially long MD simulation. To achieve this, Pande's group uses Graphic Processor Units (GPUs) of the kind that are found in video game modules. Over the last few years these units have made interesting biological phenomena accessible to chemists. C & EN has a nice article on the increasing use of GPUs for biomolecular simulation.
Pande's group also uses a set of statistical tools called Markov State Models (MSMs) to identify metastable folding states and the transition trajectories between them. MSMs provide a nifty strategy to bridge the results from several short trajectories (rather than running one long one).
What is endearing about the simulation is that that the correct structure doesn't form until much later and then quickly falls in place, like a lost kid suddenly remembering his place in the marching band. As can be seen in the video below, the missing piece of the puzzle is a short C-terminal part of a beta-sheet which seems to linger as part of an alpha helix while the rest of the sheet structure forms. After comfortably waltzing around as a little helical piece for a long time, it seems to suddenly remember its correct identity and snaps and collapses into place as part of the beta sheet. Very nice!
Admittedly, a 39 residue protein is minuscule compared to most typical proteins. But the results provide a neat proof of concept. Importantly, they also show that current force fields with implicit solvent models can be accurate enough for this kind of simulation. Further validation will test these force fields more stringently.
Voelz VA, Bowman GR, Beauchamp K, & Pande VS (2010). Molecular simulation of ab initio protein folding for a millisecond folder NTL9(1-39). Journal of the American Chemical Society, 132 (5), 1526-8 PMID: 20070076