Conformational Heterogeneity of the Calmodulin Binding Interface
- Type of resource
- software, multimedia
- Date created
- [ca. 2014]
- Calmodulin is a ubiquitous Ca2+ sensor and a crucial signaling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signaling molecules including GPCRs, ion channels, and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of calmodulin binding diversity. Our computational model indicates that in the absence of Ca2+, substates in the folded ensemble of calmodulin’s C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and thus a candidate for pharmacological intervention.
- Preferred Citation
- Shukla, D., Peck, A., and Pande, V.S. (2016). Conformational Heterogeneity of the Calmodulin Binding Interface. Stanford Digital Repository. Available at: http://purl.stanford.edu/zw177zm0384
- Related Publication
- Shukla, D., Peck, A., & Pande, V.S. Conformational heterogeneity of the calmodulin binding interface. Nat. Commun. 7:10910 doi:10.1038/ncomms10910 (2016). Available at: http://www.nature.com/ncomms/2016/160404/ncomms10910/full/ncomms10910.html
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