Abstract
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 C (NtrC). By employing unbiased Markov state model-based molecular dynamics simulations, we construct a dynamic picture of the activation pathways of this key bacterial signalling protein that is consistent with experimental observations and predicts new mutants that could be used for validation of the mechanism. Moreover, these results suggest a novel mechanistic paradigm for conformational switching.
Highlights
Recent successes in simulating protein structure and folding dynamics have demonstrated the power of molecular dynamics to predict the long timescale behaviour of proteins
For nitrogen regulatory protein C (NtrC) activation, we find that the molecular switches are all connected and can induce a sequential triggering of switches, such as T82-Y101 hydrogen bond breakage preceding rearrangement of the hydrophobic surface
The mechanism of global conformational change associated with NtrC activation lies between a sequential and cooperative mode of molecular switching so that the system is ‘functionally concerted’
Summary
Recent successes in simulating protein structure and folding dynamics have demonstrated the power of molecular dynamics to predict the long timescale behaviour of proteins. By employing unbiased Markov state model-based molecular dynamics simulations, we construct a dynamic picture of the activation pathways of this key bacterial signalling protein that is consistent with experimental observations and predicts new mutants that could be used for validation of the mechanism These results suggest a novel mechanistic paradigm for conformational switching. We propose that atomistic simulations can help identify these key structural elements, and demonstrate this by examining the activation mechanism of nitrogen regulatory protein C (NtrC) This protein belongs to the family of two component regulatory systems ubiquitous in bacteria[4], in which a phosphate is transferred from a sensor kinase (NtrB) to a response regulator (NtrC)[5]. The MSM of NtrC reveals a network of molecular switches that control NtrC activation and identifies metastable states on the NtrC conformational free energy landscape that could be targeted for inhibitor design
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