Structural stability, acidity, and halide selectivity of the fluoride riboswitch recognition site

Area of Science:

• Biochemistry
• Computational Chemistry
• Molecular Biology

Background:

• Riboswitches are RNA molecules that regulate gene expression in response to small molecules.
• The fluoride riboswitch is a class of riboswitches that specifically bind fluoride ions.
• Understanding the structural and chemical basis of fluoride binding is crucial for its biological function.

Purpose of the Study:

• To investigate the stability and structural properties of the Mg(2+)/F(-)/phosphate/water cluster in the fluoride riboswitch.
• To determine the factors responsible for the halide selectivity of the fluoride riboswitch.
• To elucidate the role of metal-halide bonds in the function of fluoride-binding RNA structures.

Main Methods:

• Density Functional Theory (DFT) methods, including static and dynamic simulations.
• Analysis of cluster stability, pKa prediction, and metal-halide bond strength.
• Comparative analysis of fluoride versus chloride binding.

Main Results:

• The Mg(2+)/F(-)/phosphate/water cluster is intrinsically stable and does not require additional RNA structural support.
• The predicted pKa of the bridging water molecule is approximately 8.4.
• The fluoride riboswitch's selectivity is attributed to the stronger Mg-F bond, which maintains cluster integrity.
• Replacing fluoride with chloride leads to an unstable cluster under dynamic conditions.
• Similar findings were observed in the fluoride-inhibited pyrophosphatase, highlighting the strength of metal-fluoride bonds.

Conclusions:

• The intrinsic stability of the Mg(2+)/F(-)/phosphate/water cluster is key to fluoride riboswitch function.
• The superior strength of the Mg-F bond compared to Mg-Cl bond dictates halide selectivity.
• Fluoride's unique ability to form strong metal-halide bonds is central to its role in biological systems.