biostudies-literatureMadsen JJNIGMS NIH HHS2686-2697https://www.ebi.ac.uk/biostudies/studies/S-EPMC12414704biostudies-literatureUnknown124(16)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 certainBiophysical journalDynamic nature of Staphylococcus aureus type I signal peptidases.PMC12414704R35 GM146993Madsen JJYu WfalseDynamic nature of Staphylococcus aureus type I signal peptidases.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 certain2025-01-01T00:00:00Z2025 Aug2026-06-06T04:21:55.918Z2026-05-25T03:12:06.502ZS-EPMC124147044140479010.1016/j.bpj.2025.07.008