Molecular Dynamics Simulations Guide Chimeragenesis and Engineered Control of Chemoselectivity in Diketopiperazine Dimerases
Name
Angew Chem Int Ed - 2023 - Shende - Molecular Dynamics Simulations Guide Chimeragenesis and Engineered Control of.pdf
Description
Published version
Size
4.47 MB
Format
Adobe PDF
Checksum (MD5)
64d6d470600ad5cc4b2cfa2b81686342
Author(s)
Shende, Vikram V
Harris, Natalia R
Sanders, Jacob N
Newmister, Sean A
Khatri, Yogan
Movassaghi, Mohammad
Houk, Kendall N
Sherman, David H
Date Issued
May 8, 2023
Journal
Angewandte Chemie International Edition
Publisher
Wiley
Citation
V. V. Shende, N. R. Harris, J. N. Sanders, S. A. Newmister, Y. Khatri, M. Movassaghi, K. N. Houk, D. H. Sherman, Angew. Chem. Int. Ed. 2023, 62, e202210254; Angew. Chem. 2023, 135, e202210254.
Version
Final published version
Abstract
In the biosynthesis of the tryptophan-linked dimeric diketopiperazines (DKPs), cytochromes P450 selectively couple DKP monomers to generate a variety of intricate and isomeric frameworks. To determine the molecular basis for selectivity of these biocatalysts we obtained a high-resolution crystal structure of selective Csp2−N bond forming dimerase, AspB. Overlay of the AspB structure onto C−C and C−N bond forming homolog NzeB revealed no significant structural variance to explain their divergent chemoselectivities. Molecular dynamics (MD) simulations identified a region of NzeB with increased conformational flexibility relative to AspB, and interchange of this region along with a single active site mutation led to a variant that catalyzes exclusive C−N bond formation. MD simulations also suggest that intermolecular C−C or C−N bond formation results from a change in mechanism, supported experimentally through use of a substrate mimic.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1002/anie.202210254
