Folding Simulations of the Villin Headpiece in All-Atom Detail.

Guha Jayachandran, V. Vishal, and V. S. Pande. Journal of Chemical Physics (2006)

SUMMARY: We have developed a new method which greatly extends Folding@home’s ability to simulate long timescales. This new method (MSM) will be applied to essentially all new Folding@home projects. This paper demonstrates MSM’s applied to a challenging target — the villin headpiece.

ABSTRACT: We report on the use of large-scale distributed computing simulation and novel analysis techniques for examining the dynamics of a small protein. Matters addressed include folding rate, very long timescale kinetics, ensemble properties, and interaction with water. The target system for the study, the villin headpiece, has been of great interest to experimentalists and theorists both. Sampling totaled nearly 500 of the most extensive published to date for a system of villin’s size in explicit solvent with all atom detail and was in the form of tens of thousands of independent molecular dynamics trajectories, each several tens of nanoseconds in length. We report on kinetics sensitivity analyses that, using a set of short simulations, probed the role of water in villin’s folding and sensitivity to the simulation’s electrostatics treatment. By constructing Markovian state models from the collected data, we were able to propagate dynamics to times far beyond those directly simulated and to rapidly compute mean first passage times, long time kinetics (tens of microseconds), and evolution of ensemble property distributions over long times, otherwise currently impossible. We also tested our MSM by using it to predict the structure of villin de novo.