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Recent successes in simulating protein structure and folding dynamics have demonstrated the power of molecular dynamics to predict the long timescale behaviour of proteins. Here, we extend and improve these methods to predict molecular switches that characterize conformational change pathways between the active and inactive state of nitrogen regulatory protein…

Continuous-time Markov processes over finite state-spaces are widely used to model dynamical processes in many fields of natural and social science. Here, we introduce a maximum likelihood estimator for constructing such models from data observed at a finite time interval. This estimator is dramatically more efficient than prior approaches, enables the calcula…

The allure of a molecular dynamics simulation is that, given a sufficiently accurate force field, it can provide an atomic-level view of many interesting phenomena in biology. However, the result of a simulation is a large, high-dimensional time series that is difficult to interpret. Recent work has introduced the time-structure based Independent Components An…

Statistical modeling of long timescale dynamics with Markov state models (MSMs) has been shown to be an effective strategy for building quantitative and qualitative insight into protein folding processes. Existing methodologies, however, rely on geometric clustering using distance metrics such as root mean square deviation (RMSD), assuming that geometric simil…

Calmodulin (CaM) is a ubiquitous Ca(2+) sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simu…

After reanalyzing simulations of NuG2-a designed mutant of protein G-generated by Lindorff-Larsen et al. with time structure-based independent components analysis and Markov state models as well as performing 1.5 ms of additional sampling on Folding@home, we found an intermediate with a register-shift in one of the β-sheets that was visited along a minor …

The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines. However, approximately one-third of the human proteome is comprised of intrinsically disordered proteins and regions (IDPs/IDRs) that do not adopt a dominant well-folde…

As molecular dynamics simulations access increasingly longer time scales, complementary advances in the analysis of biomolecular time-series data are necessary. Markov state models offer a powerful framework for this analysis by describing a system’s states and the transitions between them. A recently established variational theorem for Markov state models now…

MSMBuilder is a software package for building statistical models of high-dimensional time-series data. It is designed with a particular focus on the analysis of atomistic simulations of biomolecular dynamics such as protein folding and conformational change. MSMBuilder is named for its ability to construct Markov state models (MSMs), a class of models that has…

Reaction coordinates are widely used throughout chemical physics to model and understand complex chemical transformations. We introduce a definition of the natural reaction coordinate, suitable for condensed phase and biomolecular systems, as a maximally predictive one-dimensional projection. We then show that this criterion is uniquely satisfied by a dominant…