Improvements in Markov State Model Construction Reveal Many Non-Native Interactions in the Folding of NTL9

Markov State Models (MSMs) provide an automated framework to investigate the dynamical properties of high-dimensional molecular simulations. These models can provide a human-comprehensible picture of the underlying process and have been successfully used to study protein folding, protein aggregation, protein ligand binding, and other biophysical systems. The MSM requires the construction of a discrete state-space such that two points are in the same state if they can interconvert rapidly. In the following, we suggest an improved method, which utilizes second order Independent Component Analysis (also known as time-structure based Independent Component Analysis, or tICA), to construct the state-space. We apply this method to simulations of NTL9 (provided by Lindorff-Larsen et al. Science 2011, 334, 517–520) and show that the MSM is an improvement over previously built models using conventional distance metrics. Additionally, the resulting model provides insight into the role of non-native contacts by revealing many slow time scales associated with compact, non-native states.