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Origin and Control of Chemoselectivity in Cytochrome c-Catalyzed Carbene Transfer into Si–H and N–H bonds

preprint
submitted on 24.02.2021, 17:43 and posted on 25.02.2021, 09:44 by Marc Garcia-Borràs, S. B. Jennifer Kan, Russell D. Lewis, Allison Tang, Gonzalo Jiménez-Osés, Frances H. Arnold, Kendall N. Houk

A cytochrome c heme protein was recently engineered to catalyze the formation of carbon–silicon bonds via carbene insertion into Si–H bonds, a reaction that was not previously known to be catalyzed by a protein. High chemoselectivity towards C–Si bond formation over competing C–N bond formation was achieved, although this trait was not screened for during directed evolution. Using computational and experimental tools, we now establish that activity and chemoselectivity are modulated by conformational dynamics of a protein loop that covers the substrate access to the iron-carbene active species. Mutagenesis of residues computationally predicted to control the loop conformation altered the protein’s chemoselectivity from preferred silylation to preferred amination of a substrate containing both N–H and Si–H functionalities. We demonstrate that information on protein structure and conformational dynamics, combined with knowledge of mechanism, leads to understanding of how non-natural and selective chemical transformations can be introduced into the biological world.

Funding

2018-BP-00204

PID2019-111300GA-I00

GM-124480

OCI-1053575

CBET-1937902

MCB-2016137

CTQ2015-70524-R

History

Email Address of Submitting Author

marc.garcia@udg.edu

Institution

University of Girona

Country

Spain

ORCID For Submitting Author

0000-0001-9458-1114

Declaration of Conflict of Interest

No conflict of interest

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