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Peer-reviewedCC BY 4.0Frontiers in Microbiology

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

  • Silvia Multari1,2,3
  • Marco S. Nobile3,4
  • Wenliang Zhu2
  • Achille Giacometti1,3
  • Paolo Cazzaniga5
  • Giuseppe Pezzotti3,6
6 affiliations
  1. 1Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice
  2. 2Department of Materials Chemistry, Kyoto Institute of Technology
  3. 3Biomedical Engineering Center, Kansai Medical University
  4. 4Department of Environmental Sciences, Informatics and Statistics, Ca' Foscari University of Venice
  5. 5Department of Human and Social Sciences, University of Bergamo
  6. 6European Centre for Living Technology (ECLT), Ca' Bottacin
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Abstract

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 ( SO 4 2 - ), 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.

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Cite

BibTeXRIS
BibTeX
@article{multari2026sulfate,
  title = {{Sulfate ions promote Cnm-mediated aggregation in Streptococcus mutans: molecular dynamics insights into the oral–systemic connection}},
  author = {Silvia Multari and Marco S. Nobile and Wenliang Zhu and Achille Giacometti and Paolo Cazzaniga and Giuseppe Pezzotti},
  journal = {Frontiers in Microbiology},
  year = {2026},
  month = oct,
  doi = {10.3389/fmicb.2026.1967198},
  url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.1967198/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Sulfate ions promote Cnm-mediated aggregation in Streptococcus mutans: molecular dynamics insights into the oral–systemic connection
AU  - Silvia Multari
AU  - Marco S. Nobile
AU  - Wenliang Zhu
AU  - Achille Giacometti
AU  - Paolo Cazzaniga
AU  - Giuseppe Pezzotti
PY  - 2026
DA  - 2026/10/23
JO  - Frontiers in Microbiology
DO  - 10.3389/fmicb.2026.1967198
UR  - https://www.frontiersin.org/articles/10.3389/fmicb.2026.1967198/full
AB  - 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 ( SO 4 2 - ), 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.
SN  - 1664-302X
ER  -