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Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease
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Pipatpolkai, Tanadet , Corey, Robin A., Proks, Peter , Ashcroft, Frances M. and Stansfeld, Phillip J. (2020) Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease. Communications chemistry, 3 . 147. doi:10.1038/s42004-020-00391-0 ISSN 2399-3669.
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Official URL: https://doi.org/10.1038/s42004-020-00391-0
Abstract
Membrane proteins are frequently modulated by specific protein-lipid interactions. The activation of human inward rectifying potassium (hKir) channels by phosphoinositides (PI) has been well characterised. Here, we apply a coarse-grained molecular dynamics free energy perturbation (CG-FEP) protocol to capture the energetics of binding of PI lipids to hKir channels. By using either a single- or multi-step approach, we establish a consistent value for the binding of PIP2 to hKir channels, relative to the binding of the bulk phosphatidylcholine phospholipid. Furthermore, by perturbing amino acid side chains on hKir6.2, we show that the neonatal diabetes mutation E179K increases PIP2 affinity, while the congenital hyperinsulinism mutation K67N results in a reduced affinity. We show good agreement with electrophysiological data where E179K exhibits a reduction in neomycin sensitivity, implying that PIP2 binds more tightly E179K channels. This illustrates the application of CG-FEP to compare affinities between lipid species, and for annotating amino acid residues.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology | ||||||||||||||||||||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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| Library of Congress Subject Headings (LCSH): | Membrane proteins, Potassium channels, Inositol, Phospholipids, Molecular dynamics -- Computer simulation | ||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Communications chemistry | ||||||||||||||||||||||||||||||||||||
| Publisher: | Nature Research | ||||||||||||||||||||||||||||||||||||
| ISSN: | 2399-3669 | ||||||||||||||||||||||||||||||||||||
| Official Date: | 30 October 2020 | ||||||||||||||||||||||||||||||||||||
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| Volume: | 3 | ||||||||||||||||||||||||||||||||||||
| Article Number: | 147 | ||||||||||||||||||||||||||||||||||||
| DOI: | 10.1038/s42004-020-00391-0 | ||||||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 30 September 2020 | ||||||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 5 October 2020 | ||||||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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