Finite temperature string method with umbrella sampling using path collective variables: application to secondary...

The transition of an α-helix to a β-sheet in proteins is among the most complex conformational changes seen in biomolecular systems. Due to long time scales involved in the transition, it is challenging to study such protein conformational changes using direct molecular dynamics simulations. This limitation is typically overcome using an indirect approach wherein one computes the free energy landscape associated with the transition. Computation of free energy landscapes, however, requires a suitable set of collective variables that describe the transition. In this work, we demonstrate the use of path collective variables [D. Branduardi, F. L. Gervasio and M. Parrinello, J. Chem. Phys., 2007, 126, 054103] and combine it with the finite temperature string (FTS) method [E. Weinan, W. Ren and E. Vanden-Eijnden, J. Phys. Chem. B, 2005, 109, 6688-6693] to determine the molecular mechanisms involved during the structural transition of the mini G-protein from an α-helix to a β-hairpin. The transition from the α-helix proceeds via unfolding of the terminal residues, giving rise to a β-turn unfolded intermediate to eventually form the β-hairpin. Our proposed algorithm uses umbrella sampling simulations to simulate images along the string and the weighted histogram analysis to compute the free energy along the computed transition path. This work demonstrates that the string method in combination with path collective variables can be exploited to study complex protein conformational changes such as a complete change in the secondary structure.