Transition Metal Binding Drives Folding of a Metalloregulatory Riboswitch by Modulating Conformational Flexibility at...

Area of Science:

• Molecular Biology
• Biophysics
• Computational Biology

Background:

• Transition metal ions are essential for bacterial survival.
• Metalloregulatory riboswitches enable bacteria to regulate metal ion homeostasis.
• The NiCo riboswitch specifically detects Co²⁺, Ni²⁺, and Fe²⁺ amidst high Mg²⁺ concentrations.

Purpose of the Study:

• To elucidate the molecular mechanism of Co²⁺ binding specificity in the NiCo riboswitch.
• To understand the coupling between global conformational changes and ion binding.
• To provide a basis for engineering RNA-based biosensors and antimicrobials.

Main Methods:

• Computer simulations utilizing multiresolution RNA models.
• Analysis of riboswitch folding pathways and intermediate states.
• Electronic structure calculations to probe ion-ligand interactions.

Main Results:

• The NiCo riboswitch folds via an intermediate state with a four-way junction (4WJ) forming an anionic pocket for ion binding.
• Co²⁺ binding stabilizes noncanonical G·A base pairs and promotes coaxial stacking of helices.
• Enhanced orbital interactions between conserved guanines and Co²⁺ confer high binding specificity over Mg²⁺.

Conclusions:

• The study reveals a detailed mechanism for specific divalent metal ion recognition by the NiCo riboswitch.
• Understanding these interactions facilitates the design of novel RNA-based biosensors.
• The findings contribute to developing new antimicrobial strategies targeting bacterial metal ion metabolism.