Cytotoxicity Of Alpha-Helical, Staphylococcus Aureus Psm Alpha 3 Investigated By Post-Ion-Mobility Dissociation Mass Spectrometry

Our knowledge of amyloid formation and otoxicity originating from self-assembly of alpha-helical peptides is incomplete. PSM alpha 3 is the only system where high-resolution X-ray crystallography and toxicity data are available. Oligomers of multiple alpha-helical monomers are less stable than those of beta-strands, partially due to the lack of a consistent hydrogen-bonding network. It is challenging to preserve such oligomers in the gas phase where mass-selected structural studies using ion-mobility spectrometry mass spectrometry (IMS-MS) could be performed. As the oligomers fall apart after exiting the drift cell of the mass spectrometer, novel features that have shorter (a loss of charged species) or longer (a loss of neutral species) arrival times than expected are present together with those from the intact species. By obtaining a complete data set of PSM alpha 3 peptides in solution and with n-dodecyl-beta-D-maltoside, a micelle-forming detergent, we are able to discern the dissociated from the intact oligomers and detergent-bound complexes and correlate the reported cytotoxicity to the peptide oligomeric structures and their interactions with membrane mimetics. The study sheds new insights into the interpretation of IMS-MS data from biomolecular self-assembly studies-an important and timely topic.