Computational studies of fibrillation induced selective cytotoxicity of cross-α amyloid – Phenol Soluble Modulin α3

Abstract Phenol soluble modulin (PSM) α 3, the most toxic member of α -toxin in Staphylococcus aureus bacteria, forms cross- α amyloid fibrils and is selectively toxic to the mammalian cell membranes. In this work, it has been discovered that hydrophobic interactions play a major role in fibril formation of PSM- α 3 strands, with stabilization energy of 28.7 kCal mol−1. We considered two model bilayers mimicking mammalian and bacterial cell membranes, and found that single α -helix strand penetration is energetically unfavorable in both of them. Hence, we propose a simple model using energetics to understand the reason for selective toxicity of the peptide to the mammalian cell membrane. This study, besides enhancing the understanding of PSM- α 3, can also act as a stepping stone in future drug development against S. aureus.