Unfolding dynamics of small peptides biased by constant mechanical forces

Abstract

We show how multi-ensemble Markov state models can be combined with constant-force equilibrium simulations. Besides obtaining the unfolding/folding rates, Markov state models allow gaining detailed insights into the folding dynamics and pathways through identifying folding intermediates and misfolded structures. For two specific peptides, we demonstrate that the end-to-end distance is an insufficient reaction coordinate. This problem is alleviated through constructing models with multiple collective variables, for which we employ the time-lagged independent component analysis requiring only minimal prior knowledge. Our results show that combining Markov state models with constant-force simulations is a promising strategy to bridge the gap between simulation and experiments even for medium-sized biomolecules.