BPS2026 – How calcium strengthens Staphylococcus aureus binding to eczema-affected skin

Staphylococcus aureus relies on surface adhesins to colonize human skin, yet the molecular basis of these interactions has remained unclear. Using a multiscale computational biophysics approach, we identified the target and extraordinary mechanostability of the serine-aspartate repeat protein D (SdrD). Bioinformatics and structural modeling pointed to desmoglein-1 (DSG-1) as a candidate ligand, and molecular dynamics (MD) simulations revealed that a proximal DSG-1 loop adjacent to the extracellular cadherin domain EC4 forms the primary binding interface. All-atom steered MD revealed rupture forces stabilized by aromatic interactions and an extended hydrogen-bonding network; extrapolation to experimental pulling rates places these forces in the nanonewton range. Coarse-grained MD simulations of the full SdrD:DSG-1 complex reproduced the unfolding patterns observed experimentally, while dynamical network analysis demonstrated that calcium strengthens residue correlations across DSG-1 cadherin folds, reinforcing the interface under load. Atomic force microscopy-based single-molecule and single-cell force spectroscopy confirmed these predictions, establishing DSG-1 as the physiological ligand of SdrD and identifying this bond as one of the strongest noncovalent interactions measured to date. Beyond uncovering a new adhesion mechanism, our results highlight calcium as a key regulator of bacterial binding. Notably, S. aureus takes advantage of elevated calcium levels and the altered distribution of DSG-1 in eczema lesions, exploiting a host repair pathway to anchor more effectively and enhance colonization.