De novo design of transmembrane beta-barrels
Anastassia A Vorobieva,
Jim E. Horne,
Asim K. Bera,
Cameron M. Chow,
Stacey R. Gerben,
Alyssa Q Stiving,
Sophie R Harvey,
Dagan C Marx,
Karen G Fleming,
Vicki H Wysocki,
David. J. Brockwell,
Lukas K Tamm,
Sheena E. Radford,
Posted 23 Oct 2020
bioRxiv DOI: 10.1101/2020.10.22.346965
Posted 23 Oct 2020
Transmembrane β-barrel proteins (TMBs) are of great interest for single-molecule analytical technologies since they can spontaneously fold and insert into membranes and form stable pores, but the range of pore properties that can be achieved by repurposing natural TMBs is limited. We leverage the power of de novo computational design coupled with a 'hypothesis, design and test' approach to determine TMB design principles, notably the importance of negative design to slow β-sheet assembly. We design new eight stranded TMBs, with no homology to known TMBs, that insert and fold reversibly into synthetic lipid membranes, and have NMR and X-ray crystal structures very close to the computational models. These advances should enable the custom design of pores for a wide range of applications. ### Competing Interest Statement AAV, DB and JEH are inventors on a U.S. provisional patent application submitted by the University of Washington that covers the described sequences.
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