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

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.