(493d) Conformational Heterogeneity of Protein Binding Interfaces

Recent successes in simulating protein structure and conformational dynamics have demonstrated the power of molecular dynamics to predict the long timescale behavior of proteins. However, the structural origins of a protein’s ability to bind diverse signaling molecules including hormones, downstream effectors etc. are not well understood. In this study, we investigate two key signaling proteins Calmodulin  (a ubiquitous calcium sensor and a crucial signaling hub in many pathways aberrantly activated in disease) and nitrogen regulatory protein C (NtrC, a key bacterial two component response regulator).^1,2 By employing unbiased Markov state model-based distributed molecular dynamics simulations (total sampling of over 2 milliseconds), we construct a dynamic picture of the activation pathways of these proteins 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 and predict new binding interfaces that could be candidates for pharmacological intervention.

References:

1. A network of molecular switches controls the activation of the two-component response regulator NtrC. D. Vanatta, D. Shukla, M. Lawrenz  and V. S. Pande, Nature Communications, In press, 2015.
2. Conformational Heterogeneity of the Calmodulin Binding Interface. D. Shukla, A. Peck and V. S. Pande, Nature Communications, under review, 2015.