Rational Design Principles for De Novo α-Helical Peptide Barrels with Dynamic Conductive Channels

• DOI: 10.1021/jacs.4c13933
• Publication Date: 2025-03-28T12:02:18Z
• Authors: Ai Niitsu; Andrew R. Thomson; Alistair J. Scott; Jason T. Sengel; Jaewoon Jung; Kozhinjampara R. ...; Mikiko Sodeoka; Hagan Bayley; Yuji Sugita; Derek N. Woolfson; Mark I. Wallace
• Keywords: Rational design; Cyclic peptide

Despite advances in peptide and protein design, the rational design of membrane-spanning peptides that form conducting channels remains challenging due to our imperfect understanding sequence-to-structure relationships drive membrane insertion, assembly, conductance. Here, we describe computational experimental characterization a series coiled coil-based transmembrane α-helical barrels with conductive channels. Through combination obtain 5 7 helices, as characterized detergent micelles. In lipid bilayers, these assemblies exhibit two conductance states relative populations dependent on applied potential: (i) low-conductance correlate variations designed amino-acid sequences modeled coiled-coil barrel geometries, indicating stable barrels; (ii) high-conductance which single change size discrete steps. Notably, are similar for all contrast states. This indicates formation large, dynamic channels, observed natural barrel-stave These findings establish routes tune functional specific geometry.