Sulfate ions promote Cnm-mediated aggregation in Streptococcus mutans: molecular dynamics insights into the oral–systemic connection

The collagen-binding protein Cnm from Streptococcus mutans has been implicated in cerebral microbleeds, a pathological condition frequently associated with ischemic stroke. Recent experimental evidence suggests that Cnm-mediated interactions may drive protein–protein aggregation, with the potential influence of ionic environment. In this work, we attempt to shed light on this issue by studying the molecular origin determinants of Cnm–Cnm association using a multiscale molecular dynamics approach. All-atom simulations were performed to evaluate the effect of sulfate ions (SO2^−4), selected based on the experimentally observed enrichment of sulfur-containing species in Cnm-positive S. mutans, on the stability of the complex. To extend the analysis to larger sizes and longer timescales, additional coarse-grained simulations using MARTINI force field were first implemented and validated against the atomistic reference, and subsequently used to explore the thermodynamics of protein–protein association. Our results indicate that sulfate ions significantly enhance the stability of the Cnm–Cnm complex, as evidenced by reduced fluctuations in the inter-protein distance, an increased number of intermolecular contacts, and a deeper minimum in the binding free-energy profile. These findings suggest that ionic screening can indirectly promote Cnm aggregation, providing physical mechanistic insights to aggregation processes potentially relevant to S. mutans pathogenicity.