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I02-Macromolecular Crystallography	Computational design of transmembrane pores Chunfu Xu , Peilong Lu , Tamer M. Gamal El-Din , Xue Y. Pei , Matthew C. Johnson , Atsuko Uyeda , Matthew J. Bick , Qi Xu , Daohua Jiang , Hua Bai , Gabriella Reggiano , Yang Hsia , T. J. Brunette , Jiayi Dou , Dan Ma , Eric M. Lynch , Scott E. Boyken , Po-Ssu Huang , Lance Stewart , Frank Dimaio , Justin M. Kollman , Ben Luisi , Tomoaki Matsuura , William A. Catterall , David Baker Nature 585, 129 - 134 DOI: 10.1038/s41586-020-2646-5 Diamond Proposal Number(s): [9537] Show Abstract ▼ Abstract: Transmembrane channels and pores have key roles in fundamental biological processes and in biotechnological applications such as DNA nanopore sequencing resulting in considerable interest in the design of pore-containing proteins. Synthetic amphiphilic peptides have been found to form ion channels, and there have been recent advances in de novo membrane protein design and in redesigning naturally occurring channel-containing proteins. However, the de novo design of stable, well-defined transmembrane protein pores that are capable of conducting ions selectively or are large enough to enable the passage of small-molecule fluorophores remains an outstanding challenge. Here we report the computational design of protein pores formed by two concentric rings of α-helices that are stable and monodisperse in both their water-soluble and their transmembrane forms. Crystal structures of the water-soluble forms of a 12-helical pore and a 16-helical pore closely match the computational design models. Patch-clamp electrophysiology experiments show that, when expressed in insect cells, the transmembrane form of the 12-helix pore enables the passage of ions across the membrane with high selectivity for potassium over sodium; ion passage is blocked by specific chemical modification at the pore entrance. When incorporated into liposomes using in vitro protein synthesis, the transmembrane form of the 16-helix pore—but not the 12-helix pore—enables the passage of biotinylated Alexa Fluor 488. A cryo-electron microscopy structure of the 16-helix transmembrane pore closely matches the design model. The ability to produce structurally and functionally well-defined transmembrane pores opens the door to the creation of designer channels and pores for a wide variety of applications.	Sep 2020

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I02-Macromolecular Crystallography

Computational design of transmembrane pores