Conformational Transitions of Histidine Kinases using Molecular Dynamics

Abstract

One of the main signal transduction mechanisms in bacteria are two-component systems (TCS), which are comprised of homodimeric sensor histidine kinase (HK) and response regulator (RR) proteins (1). Histidine kinases are multidomain, transmembrane proteins which function by detecting a stimulus and then propagate this signal across the domains via a series of conformational transitions ruled by unstable transient interactions (2), subsequently resulting in an appropriate cellular response. The dimerization histidine phosphotransfer (DHp) domain, contains a phosphorylatable conserved histidine residue. Secondly, the catalytic ATP-binding (CA) domain, binds ATP and hence provides the phosphoryl group necessary for phosphorylating the histidine residue in the DHp. Finally, the phosphoryl group from the histidine residue of the DHp of HK is transferred to an aspartate residue of the RR protein. We investigate this signal transduction using coarse-grained and all-atom molecular dynamics simulations. A specific focus are the conformational transitions between the active and inactive states of the conserved kinase core. In the active conformation, the ATP of CA and phosphorylatable histidine of DHp are in an ideal orientation for phosphoryl group transfer whereas in the inactive conformation, the two domains are too distant.