Conformational and Reaction Dynamic Coupling in Histidine Kinases. Insights from hybrid QM/MM simulations.

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. The precise mechanism leading to autophosphorylation and the coupling between conformational and chemical steps are still largely unknown. In the present work, we use several molecular simulation techniques (Molecular Dynamics, Hybrid QM/MM and constant ph MD) to study the activation and autophosphorylation reactions in L.plantarum WalK, a cis acting HK. In agreement with previous results, our results show that the chemical step, requires, a tight coupling with the conformational step in order to maintain the histidine phosphoacceptor in correct tautomeric state, with a reactive -nitro...