Computational design of chemogenetic and optogenetic split proteins

Onur Dagliyan, Andrey Krokhotin, Irem Ozkan-Dagliyan, Alexander Deiters, Channing J. Der, Klaus M. Hahn () and Nikolay V. Dokholyan ()
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Onur Dagliyan: University of North Carolina at Chapel Hill
Andrey Krokhotin: University of North Carolina at Chapel Hill
Irem Ozkan-Dagliyan: University of North Carolina at Chapel Hill
Alexander Deiters: University of Pittsburgh
Channing J. Der: University of North Carolina at Chapel Hill
Klaus M. Hahn: University of North Carolina at Chapel Hill
Nikolay V. Dokholyan: University of North Carolina at Chapel Hill

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: Abstract Controlling protein activity with chemogenetics and optogenetics has proven to be powerful for testing hypotheses regarding protein function in rapid biological processes. Controlling proteins by splitting them and then rescuing their activity through inducible reassembly offers great potential to control diverse protein activities. Building split proteins has been difficult due to spontaneous assembly, difficulty in identifying appropriate split sites, and inefficient induction of effective reassembly. Here we present an automated approach to design effective split proteins regulated by a ligand or by light (SPELL). We develop a scoring function together with an engineered domain to enable reassembly of protein halves with high efficiency and with reduced spontaneous assembly. We demonstrate SPELL by applying it to proteins of various shapes and sizes in living cells. The SPELL server (spell.dokhlab.org) offers an automated prediction of split sites.

Date: 2018
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DOI: 10.1038/s41467-018-06531-4

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