The Fip35 WW domain folds with structural and mechanistic heterogeneity in molecular dynamics simulations

Abstract

We describe molecular dynamics simulations resulting in the folding the Fip35 Hpin1 WW domain. The simulations were run on a distributed set of graphics processors, which are capable of providing up to two orders of magnitude faster computation than conventional processors. Using the Folding@home distributed computing system, we generated thousands of independent trajectories in an implicit solvent model, totaling over 2.73 ms of simulations. A small number of these trajectories folded; the folding proceeded along several distinct routes and the system folded into two distinct three-stranded beta-sheet conformations, showing that the folding mechanism of this system is distinctly heterogeneous.

Figure 1

Five folded structures from the four trajectories started in unfolded configurations and one inverted structure. In the following, two Cα RMSD values are listed: one for all α-carbons and one for the β sheet residues. (a) T300-γ1, 3.832 Å, 0.491 Å, (b) T300-γ1, 6.300 Å, 2.639 Å, (c) T330-γ1, 7.444 Å, 1.722 Å, (d) T330-γ1, 6.492 Å, 2.004 Å, and (e) T300-γ1, 6.866 Å, 2.370 Å. The structures shown were those from each solvent condition with the lowest Cα RMSD for the β sheet. Structure e is misthreaded.

Figure 2

Four folding trajectories from (a) T300-γ91, (b) T300-γ1, (c), and (d) T330-γ1. Each proceeds by a distinct mechanism.