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 F. Luisi, Tomoaki Matsuura, William A. Catterall () and David Baker ()
Additional contact information
Chunfu Xu: University of Washington
Peilong Lu: University of Washington
Tamer M. Gamal El-Din: University of Washington
Xue Y. Pei: University of Cambridge
Matthew C. Johnson: University of Washington
Atsuko Uyeda: Osaka University
Matthew J. Bick: University of Washington
Qi Xu: Westlake University
Daohua Jiang: University of Washington
Hua Bai: University of Washington
Gabriella Reggiano: University of Washington
Yang Hsia: University of Washington
T J Brunette: University of Washington
Jiayi Dou: University of Washington
Dan Ma: Westlake University
Eric M. Lynch: University of Washington
Scott E. Boyken: University of Washington
Po-Ssu Huang: University of Washington
Lance Stewart: University of Washington
Frank DiMaio: University of Washington
Justin M. Kollman: University of Washington
Ben F. Luisi: University of Cambridge
Tomoaki Matsuura: Osaka University
William A. Catterall: University of Washington
David Baker: University of Washington

Nature, 2020, vol. 585, issue 7823, 129-134

Abstract: Abstract Transmembrane channels and pores have key roles in fundamental biological processes1 and in biotechnological applications such as DNA nanopore sequencing2–4, resulting in considerable interest in the design of pore-containing proteins. Synthetic amphiphilic peptides have been found to form ion channels5,6, and there have been recent advances in de novo membrane protein design7,8 and in redesigning naturally occurring channel-containing proteins9,10. 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 challenge11,12. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2646-5

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