The opportunistic pathogen Staphylococcus epidermidis utilizes a multidomain surface adhesin protein to bind host components and adhere to tissues. While it is known that the interaction between the SdrG receptor and its fibrinopeptide target (FgB) is exceptionally mechanostable (∼2 nN), the influence of downstream B domains (B1 and B2) is unclear. Here, we studied the mechanical relationships between folded B domains and the SdrG receptor bound to FgB. We used protein engineering, single-molecule force spectroscopy (SMFS) with an atomic force microscope (AFM), and Monte Carlo simulations to understand how the mechanical properties of folded sacrificial domains, in general, can be optimally tuned to match the stability of a receptor-ligand complex. Analogous to macroscopic suspension systems, sacrificial shock absorber domains should neither be too weak nor too strong to optimally dissipate mechanical energy. We built artificial molecular shock absorber systems based on the nanobody (VHH) scaffold and studied the competition between domain unfolding and receptor unbinding. We quantitatively determined the optimal stability of shock absorbers that maximizes work dissipation on average for a given receptor and found that natural sacrificial domains from pathogenic S. epidermidis and Clostridium perfringens adhesins exhibit stabilities at or near this optimum within a specific range of loading rates. These findings demonstrate how tuning the stability of sacrificial domains in adhesive polyproteins can be used to maximize mechanical work dissipation and serve as an adhesion strategy by bacteria.
© 2022 The Authors. Published by American Chemical Society.