info:eu-repo/semantics/article
Conformational and Reaction Dynamic Coupling in Histidine Kinases: Insights from Hybrid QM/MM Simulations
Fecha
2020-02Registro en:
Olivieri, Federico Alberto; Burastero, Osvaldo; Drusin, Salvador Iván; Defelipe, Lucas Alfredo; Wetzler, Diana Elena; et al.; Conformational and Reaction Dynamic Coupling in Histidine Kinases: Insights from Hybrid QM/MM Simulations; American Chemical Society; Journal of Chemical Information and Modeling; 60; 2; 2-2020; 833-842
1549-9596
CONICET Digital
CONICET
Autor
Olivieri, Federico Alberto
Burastero, Osvaldo
Drusin, Salvador Iván
Defelipe, Lucas Alfredo
Wetzler, Diana Elena
Turjanski, Adrian
Marti, Marcelo Adrian
Resumen
Histidine kinases (HK) of bacterial two-component systems represent a hallmark of allosterism in proteins, being able to detect a signal through the sensor domain and transmit this information through the protein matrix to the kinase domain which, once active, autophosphorylates a specific histidine residue. Inactive-to-active transition results in a large conformational change that moves the kinase on top of the histidine. In the present work, we use several molecular simulation techniques (Molecular Dynamics, Hybrid QM/MM, and constant pH molecular dynamics) to study the activation and autophosphorylation reactions in L. plantarum WalK, a cis-acting HK. In agreement with previous results, we show that the chemical step requires tight coupling with the conformational step in order to maintain the histidine phosphoacceptor in the correct tautomeric state, with a reactive δ-nitrogen. During the conformational transition, the kinase domain is never released and walks along the HK helix axis, breaking and forming several conserved residue-based contacts. The phosphate transfer reaction is concerted in the transition state region and is catalyzed through the stabilization of the negative developing charge of transferring phosphate along the reaction.