Deciphering the Catalytic Mechanism of Virginiamycin B Lyase with Multiscale Methods and Molecular Dynamics Simulations

• Tipo: Artigo em Revista Científica Internacional
• Data: 2023

Autores

Coimbra, JTS (Autor) Outra; Pedro A Fernandes (Autor) FCUP; Ramos, MJ (Autor) FCUP

Revista

Título: Journal of Chemical Information and Modeling

Vol. 63

Páginas: 6354-6365

ISSN: 1549-9596

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 0 Citações

Scopus - 0 Citações

Outras Informações

ID Authenticus: P-00Z-ADP

DOI: 10.1021/acs.jcim.3c00962

Abstract (EN): Due to the emergence of antibiotic resistance, the need to explore novel antibiotics and/or novel strategies to counter antibiotic resistance is of utmost importance. In this work, we explored the molecular and mechanistic details of the degradation of a streptogramin B antibiotic by virginiamycin B (Vgb) lyase of Staphylococcus aureus using classical molecular dynamics simulations and multiscale quantum mechanics/molecular mechanics methods. Our results were in line with available experimental kinetic information. Although we were able to identify a stepwise mechanism, in the wild-type enzyme, the intermediate is short-lived, showing a small barrier to decay to the product state. The impact of point mutations on the reaction was also assessed, showing not only the importance of active site residues to the reaction catalyzed by Vgb lyase but also of near positive and negative residues surrounding the active site. Using molecular dynamics simulations, we also predicted the most likely protonation state of the 3-hydroxypicolinic moiety of the antibiotic and the impact of mutants on antibiotic binding. All this information will expand our understanding of linearization reactions of cyclic antibiotics, which are crucial for the development of novel strategies that aim to tackle antibiotic resistance.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12