Conformational change induced by binding of Mn2+ ions activates SloR transcription factor in Streptococcus mutans.

Streptococcus mutans, a bacterium commonly found in the human oral cavity, is considered the primary causative agent of dental caries. A key player in the pathophysiology of S. mutans is SloR, a 25-kDa metalloregulatory protein. SloR plays a crucial role in coordinating the uptake of essential metal ions, particularly manganese, with the transcription of the bacterium's virulence genes. To elucidate the molecular mechanism underlying the enhanced binding affinity of SloR to DNA upon Mn2+ ion binding, a combination of computational (QM and MD) and experimental (ITC, DSC, CD, EPR) methods have been employed. Computational simulations revealed that Mn2+ binding induces a conformational change of SloR, primarily affecting the positioning of its DNA-binding domains, bringing them to an appropriate position for DNA binding. Consequently, the protein's DNA binding affinity is modulated. Additionally, experimental findings indicate that the SloR monomer binds up to three Mn2+ ions and that the thermodynamic stability of SloR increases upon Mn2+ complexation. The presented computational results also suggest that Mn2+ binding at the primary binding sites is sufficient to trigger the observed conformational change in SloR.