BPS2026 – Calcium coordination enhances protein mechanostability through polarization effects

Calcium ions are ubiquitous stabilizers of protein structure, frequently found in the most mechanically resilient protein folds. A striking example is the B-domain of Staphylococcus aureus SdrD, whose extreme mechanostability is strongly influenced by calcium coordination. To investigate the molecular basis of this behavior, we combined steered molecular dynamics (SMD) pulling simulations with single-molecule force spectroscopy data. Simulations performed across six pulling velocities using the CHARMM force field underestimated rupture forces at low loading rates when compared to AFM experiments. Because metal coordination can be sensitive to polarization effects, we tested four force fields: two non-polarizable (CHARMM, AMBER) and two polarizable (AMOEBA, Drude), all under the same SMD parameters. While non-polarizable models produced nearly identical results, the polarizable models increased unfolding forces by up to ∼15%, improving agreement with experiments and suggesting alternative unfolding pathways. These findings highlight the role of calcium coordination and polarization in shaping protein energy landscapes, advancing our understanding of force-dependent stability in pathogen adhesion.