Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants
- Creators
-
Einav, Tal
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Phillips, Rob
Abstract
We present a framework for computing the gating properties of ligand-gated ion channel mutants using the Monod-Wyman-Changeux (MWC) model of allostery. We derive simple analytic formulas for key functional properties such as the leakiness, dynamic range, half-maximal effective concentration ([EC_(50)]), and effective Hill coefficient, and explore the full spectrum of phenotypes that are accessible through mutations. Specifically, we consider mutations in the channel pore of nicotinic acetylcholine receptor (nAChR) and the ligand binding domain of a cyclic nucleotide-gated (CNG) ion channel, demonstrating how each mutation can be characterized as only affecting a subset of the biophysical parameters. In addition, we show how the unifying perspective offered by the MWC model allows us, perhaps surprisingly, to collapse the plethora of dose-response data from different classes of ion channels into a universal family of curves.
Additional Information
© 2017 American Chemical Society. Received: December 16, 2016; Revised: January 28, 2017; Published: January 30, 2017. It is with sadness that we dedicate this paper to the memory of Klaus Schulten with whom one of us (RP) wrote his first paper in biophysics. Klaus was an extremely open and kind man, a broad and deep thinker who will be deeply missed. We thank Stephanie Barnes, Nathan Belliveau, Chico Camargo, Griffin Chure, Vahe Galstyan, Lea Goentoro, Michael Manhart, Chris Miller, Muir Morrison, Manuel Razo-Mejia, Noah Olsman, Allyson Sgro, and Jorge Zañudo for their sharp insights and valuable feedback on this work. We are also grateful to Henry Lester, Klaus Benndorf, and Vasilica Nache for helpful discussions as well as sharing their ion channel data. All plots were made in Mathematica using the CustomTicks package. This work was supported by La Fondation Pierre-Gilles de Gennes, the Rosen Center at Caltech, the National Science Foundation under NSF PHY11-25915 at the Kavli Center for Theoretical Physics, and the National Institutes of Health through DP1 OD000217 (Director's Pioneer Award), 5R01 GM084211C, R01 GM085286, and 1R35 GM118043-01 (MIRA).Attached Files
Accepted Version - acs_2Ejpcb_2E6b12672.pdf
Accepted Version - nihms857725.pdf
Submitted - 102194.full.pdf
Submitted - 1701.06122.pdf
Supplemental Material - jp6b12672_si_001.pdf
Supplemental Material - jp6b12672_si_002.zip
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Additional details
- PMCID
- PMC5551692
- Eprint ID
- 73863
- Resolver ID
- CaltechAUTHORS:20170131-092637914
- La Fondation Pierre-Gilles de Gennes
- Caltech
- NSF
- PHY11-25915
- NIH
- DP1 OD000217
- NIH
- 5R01 GM084211C
- NIH
- R01 GM085286
- NIH
- 1R35 GM118043-01
- Created
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2017-01-31Created from EPrint's datestamp field
- Updated
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2022-04-04Created from EPrint's last_modified field
- Caltech groups
- Kavli Nanoscience Institute