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The role of protein environment in catalysis by biotinylated secondary amines

Nodling, Alexander Roland, Santi, Nicolò ORCID: https://orcid.org/0000-0001-6361-5457, Castillo, Raquel, Lipka-Lloyd, Magdalena, Jin, Yi ORCID: https://orcid.org/0000-0002-6927-4371, Morrill, Louis Christian ORCID: https://orcid.org/0000-0002-6453-7531, Swiderek, Katarzyna, Moliner, Vicent and Luk, Louis Y. P. ORCID: https://orcid.org/0000-0002-7864-6261 2021. The role of protein environment in catalysis by biotinylated secondary amines. Organic and Biomolecular Chemistry 19 , pp. 10424-10431. 10.1039/D1OB01947C

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Abstract

Here, we combine the use of host screening, protein crystallography and QM/MM molecular dynamics simulations to investigate how protein binding affects catalysis by biotinylated secondary amines. Monomeric streptavidin (M-Sav) lacks a quaternary structure and the solvent-exposed reaction site resulted in poor product conversion for the model reaction with low enantio- and regioselectivity. These parameters were much improved when the tetrameric host T-Sav was used; indeed, residues at the symmetrical subunit interface were proven to be critical for catalysis through mutagenesis study. Use of QM/MM simulations and the asymmetric dimeric variant D-Sav revealed that both Lys121 residues which located in the hosting and neighboring subunits play critical role in dictating the stereoselectivity and reactivity. Lastly, we viewed that the D-Sav template, though offering a lower conversion than that of the symmetric tetrameric counterpart, is likely a better starting point for future protein engineering because each surrounding residue within the asymmetric scaffold can be refined for secondary amine catalysis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Royal Society of Chemistry
ISSN: 1477-0520
Funders: Wellcome Trust and Leverhulme Trust
Date of First Compliant Deposit: 16 November 2021
Date of Acceptance: 14 November 2021
Last Modified: 29 Nov 2022 10:08
URI: https://orca.cardiff.ac.uk/id/eprint/145549

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