Kinetics and mechanism of the unfolding native-to-loop transition of Trp-cage in explicit solvent via optimized forward flux sampling simulations.

The native-to-loop (N-L) unfolding transition of Trp-cage protein was studied via optimized forward flux sampling (FFS) methods with trajectories evolved using molecular dynamics. The rate constant calculated from our simulations is in good agreement with the experimental value for the native-to-unfolded transition of this protein; furthermore, the trajectories sampled a phase region consistent with that reported in previous studies for the N-L transition using transition path sampling and transition interface sampling. A new variant of FFS is proposed and implemented that allows a better control of a constant flux of partial paths. A reaction coordinate model was obtained, at no extra cost, from the transition path ensemble generated by FFS, through iterative use of the FFS-least-square estimation method [E. E. Borrero and F. A. Escobedo, J. Chem. Phys. 127, 164101 (2007)] and an adaptive staging optimization algorithm [E. E. Borrero and F. A. Escobedo, J. Chem. Phys. 129, 024115 (2008)]. Finally, we further elucidate the unfolding mechanism by correlating the unfolding progress with changes in the root mean square deviation from the α carbons of the native state, the root mean square deviation from an ideal α-helix, and other structural properties of the protein.