Constructing ion channels from water-soluble α-helical barrels

Scott, A. J. et al. (2021) Constructing ion channels from water-soluble α-helical barrels. Nature Chemistry, 13(7), pp. 643-650. (doi: 10.1038/s41557-021-00688-0) (PMID:33972753) (PMCID:PMC7611114)

Abstract

The design of peptides that assemble in membranes to form functional ion channels is challenging. Specifically, hydrophobic interactions must be designed between the peptides and at the peptide–lipid interfaces simultaneously. Here, we take a multi-step approach towards this problem. First, we use rational de novo design to generate water-soluble α-helical barrels with polar interiors, and confirm their structures using high-resolution X-ray crystallography. These α-helical barrels have water-filled lumens like those of transmembrane channels. Next, we modify the sequences to facilitate their insertion into lipid bilayers. Single-channel electrical recordings and fluorescent imaging of the peptides in membranes show monodisperse, cation-selective channels of unitary conductance. Surprisingly, however, an X-ray structure solved from the lipidic cubic phase for one peptide reveals an alternative state with tightly packed helices and a constricted channel. To reconcile these observations, we perform computational analyses to compare the properties of possible different states of the peptide.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Thomson, Dr Drew
• Authors: Scott, A. J., Niitsu, A., Kratochvil, H. T., Lang, E. J. M., Sengel, J. T., Dawson, W. M., Mahendran, K. R., Mravic, M., Thomson, A. R., Brady, R. L., Liu, L., Mulholland, A. J., Bayley, H., DeGrado, W. F., Wallace, M. I., and Woolfson, D. N.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Nature Chemistry
• Publisher: Nature Research
• ISSN: 1755-4330
• ISSN (Online): 1755-4349
• Published Online: 10 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Chemistry 13(7): 643-650
• Publisher Policy: Reproduced in accordance with the publisher copyright policy
• Data DOI: 10.6084/m9.figshare.14406419