Molecular Dynamics Simulations Guide Chimeragenesis and Engineered Control of Chemoselectivity in Diketopiperazine Dimerases.
Angew Chem Int Ed Engl
; 62(20): e202210254, 2023 05 08.
Article
en En
| MEDLINE
| ID: mdl-36610039
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Dicetopiperazinas
/
Simulación de Dinámica Molecular
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos