Abstract
Molecular dynamics simulations are used to interrogate the dynamic nature of Staphylococcus aureus type I signal peptidases, SpsA and SpsB, including the impact of the P29S mutation of SpsB. Fluctuations and plasticity-rigidity characteristics vary among the proteins, particularly in the extracellular domain. Intriguingly, the P29S mutation, which influences susceptibility to arylomycin antibiotics, affects the mechanically coupled motions in SpsB. The integrity of the active site is crucial for catalytic competency, and variations in sampled structural conformations among the proteins are consistent with diverse peptidase capabilities among the two SpsB variants. We also explored the intricate interactions between the proteins and the model S. aureus membrane. It was observed that certain membrane-inserted residues in the loop around residue 50 (50s) and C-terminal loops, beyond the transmembrane domain, give rise to direct interactions with lipids in the bilayer membrane. Our findings are discussed in the context of functional knowledge about these signal peptidases, offering additional understanding of dynamic aspects relevant to some cellular processes with potential implications for drug targeting strategies and future experimental validation.