Membrane-spanning α-helical barrels as tractable protein-design targets

<jats:p> The rational ( <jats:italic>de novo</jats:italic> ) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of ‘scaffolds’ for protein design, and the means to garner sequence-to-structure relationships to guide the design process. The α-helical coiled coil is a protein-structure element found in both globular and membrane proteins, where it cements a variety of helix–helix interactions and helical bundles. Our deep understanding of coiled coils has enabled a large number of successful <jats:italic>de novo</jats:italic> designs. For one class, the α-helical barrels—that is, symmetric bundles of five or more helices with central accessible channels—there are both water-soluble and membrane-spanning examples. Recent computational designs of water-soluble α-helical barrels with five to seven helices have advanced the design field considerably. Here we identify and classify analogous and more complicated membrane-spanning α-helical barrels from the Protein Data Bank. These provide tantalizing but tractable targets for protein engineering and <jats:italic>de novo</jats:italic> protein design. </jats:p> <jats:p>This article is part of the themed issue ‘Membrane pores: from structure and assembly, to medicine and technology’.</jats:p>