Markov state model for the forced unfolding of a small peptide.

Abstract

The mechanical unfolding of molecular complexes or biomolecules can routinely be studied using methods of single molecule force spectroscopy. In particular, the application of a force ramp with a constant pulling velocity in conjunction with stochastic modeling can be used to obtain valuable information regarding the relevant kinetics and the energy landscape. The computational counterpart of this type of experiment, using molecular dynamics simulations with atomistic resolution, allows us to gain insights into the molecular rearrangements underlying the unfolding process. However, due to the large difference in time scales, often coarse graining procedures are applied in the simulations. Most of the utilized techniques do not allow us to follow the atomistic details of the relevant conformational transitions due to the structural simplifications used to speed up the simulations. Here, we apply an earlier developed dynamic coarse graining technique based on Markov state modeling to a model peptidic system that does not unfold in a simple two-state manner. Using the donor-acceptor distances of the helical hydrogen bonds as collective variables and performing a dimension reduction allows us to construct a Markov model of the unfolding process that correctly represents the microscopic behavior of the system for not too fast pulling velocities. The chosen example shows that the method can be used to mimic the mechanical unfolding process of systems for which the end-to-end distance does not provide a sufficient order parameter and that do not unfold in a simple cooperative manner.

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