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Molecular dynamics simulations have the potential to provide atomic-level detail and insight to important questions in chemical physics that cannot be observed in typical experiments. However, simply generating a long trajectory is insufficient, as researchers must be able to transform the data in a simulation trajectory into specific scientific insights. Alth…

CONSPECTUS: Protein function is inextricably linked to protein dynamics. As we move from a static structural picture to a dynamic ensemble view of protein structure and function, novel computational paradigms are required for observing and understanding conformational dynamics of proteins and its functional implications. In principle, molecular dynamics simula…

Chaperonins are large ring shaped oligomers that facilitate protein folding by encapsulation within a central cavity. All chaperonins possess flexible C-termini which protrude from the equatorial domain of each subunit into the central cavity. Biochemical evidence suggests that the termini play an important role in the allosteric regulation of the ATPase cycle…

In broad terms, percolation theory describes the conditions under which clusters of nodes are fully connected in a random network. A percolation phase transition occurs when, as edges are added to a network, its largest connected cluster abruptly jumps from insignificance to complete dominance. In this article, we apply percolation theory to meticulously const…

The interconversion between inactive and active protein states, traditionally described by two static structures, is at the heart of signalling. However, how folded states interconvert is largely unknown due to the inability to experimentally observe transition pathways. Here we explore the free energy landscape of the bacterial response regulator NtrC by comb…

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…