Biophysical Society Thematic Meeting | Ascona 2026

Mechanobiology of Infection

Tuesday Speaker Abstracts

MECHANICAL STABILITY DRIVES ADHESION AND VIRULENCE EVOLUTION IN STAPHYLOCOCCUS AUREUS Rafael C Bernardi Auburn University, Department of Physics, Auburn, AL, USA Mechanical forces are central to host–pathogen interactions, yet the molecular principles that enable bacteria to withstand these forces during infection remain poorly understood. Staphylococcus aureus relies on a large family of surface adhesins, known as MSCRAMMs, to establish initial contact with host tissues, a critical step preceding biofilm formation and persistent infection. These adhesins share a conserved architecture in which A-domains, composed of tandem immunoglobulin-like folds (N2 and N3), mediate adhesion through a dock– lock–latch (DLL) mechanism that forms exceptionally strong non-covalent bonds, while adjacent B-domains act as extensible, Ig-like modules proposed to function as molecular shock absorbers. Here, we use large-scale molecular dynamics simulations combined with dynamic network analysis to characterize the mechanostability of MSCRAMM adhesins at the molecular level and to uncover how this stability is regulated and evolves. Our results show that calcium coordination plays a central role in reinforcing the mechanical response of these proteins and may act as a regulatory switch that modulates the function of B-domains, enhancing their effectiveness as shock absorbers under high force loading rates, particularly in physiologically relevant environments such as the skin. Building on this mechanistic insight, comparative simulations across historical and clinical isolates reveal a clear evolutionary trend: adhesins from modern MRSA strains exhibit significantly greater mechanoresilience than those from MSSA strains and early 20th-century isolates collected prior to the widespread use of antibiotics. At the molecular level, dynamic network analysis reveals that force propagation through these complexes is highly coordinated across the A-domains, with more virulent strains displaying increased rigidity and connectivity in their allosteric networks, suggesting a more efficient transmission of mechanical stress across the protein. Importantly, these computational predictions are supported by single-molecule force spectroscopy experiments from collaborators, confirming that MRSA adhesins are mechanically stronger than those of MSSA. Together, these results establish a direct link between molecular-scale mechanical stability and bacterial virulence, indicating that S. aureus adhesins are actively evolving toward increased resistance to mechanical stress. More broadly, this work demonstrates how state-of-the-art computational biophysics approaches, integrating molecular dynamics simulations with network-based analysis, provide a powerful framework to uncover the mechanistic basis of mechanobiology in infection and to understand how mechanical forces shape the evolution of pathogenic traits.

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