Segmented Transition Pathway of the Signaling Protein Nitrogen Regulatory Protein C

Recent advances in exptl. methods provide increasing evidence that proteins sample the conformational substates that are important for function in the absence of their ligands. An example is the receiver domain of nitrogen regulatory protein C (NtrC)​, a member of the phosphorylation-​mediated signaling family of "two-​component systems.". The receiver domain of nitrogen regulatory protein C (NtrCR) samples both inactive conformation and the active conformation before phosphorylation. Here we det. a possible pathway of interconversion between the active state and the inactive state by targeted mol. dynamics (TMD) simulations and quasi-​harmonic anal. (QHA)​; these methods are used because the exptl. conversion rate is in the high microsecond range, longer than those that are easily accessible to atomistic mol. dynamics simulations. The calcd. pathway is found to be composed of four consecutive stages described by different progress variables. The lowest quasi-​harmonic principal components from unbiased mol. dynamics simulations on the active state correspond to the first stage, but not to the subsequent stages of the transition. The targeted mol. dynamics pathway suggests that several transient nonnative hydrogen bonds may facilitate the transition.