Transition metal ions are crucial for bacteria's survival. Bacteria employ metalloregulatory riboswitches to respond to varying metal ion concentrations. The czcD (NiCo) transcription riboswitch specifically senses Co 2+ , Ni 2+ , and Fe 2+ ions at micromolar concentrations amid millimolar Mg 2+ . We used computer simulations with multi-resolution RNA models to understand how global conformational changes in the NiCo riboswitch are coupled to the remarkable specific binding of Co 2+ . We show that the riboswitch folds through an intermediate state, where a partially folded four-way junction (4WJ) creates an anionic pocket large enough to accommodate the binding of solvated divalent ions. The binding of Co 2+ is coupled to the stability of the weak non-canonical G·A base pairs at the helical junction that drive the formation of native-like coaxial stacking of four helices. The Co 2+ binding further twists the 4WJ, which locks the ions in the bound state. Electronic structure calculations show that enhanced orbital interactions between conserved guanines in the 4WJ and Co 2+ are responsible for the high specificity of the riboswitch in binding to Co 2+ over Mg 2+ . We provide a framework for understanding and engineering tunable RNA-based biosensors and developing antimicrobials, as metal intoxication is an evolutionary strategy to inhibit bacterial growth.
Mondal et al. (Sat,) studied this question.