Conformational Heterogeneity of the Calmodulin Binding Interface
Abstract/Contents
- Abstract
- 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.
Description
| Type of resource | software, multimedia |
|---|---|
| Date created | [ca. 2014] |
Creators/Contributors
| Author | Shukla, Diwakar | |
|---|---|---|
| Author | Peck, Ariana | |
| Principal investigator | Pande, Vijay |
Subjects
| Subject | conformational change |
|---|---|
| Subject | calmodulin |
| Subject | Markov State Model |
| Genre | Dataset |
Bibliographic information
| 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 |
|---|---|
| Location | https://purl.stanford.edu/zw177zm0384 |
Access conditions
- Use and reproduction
- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
Preferred citation
- 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
Collection
Folding@home Collection
View other items in this collection in SearchWorksContact information
- Contact
- apeck@stanford.edu
Also listed in
Loading usage metrics...