A Molecular Dynamics Study of the Short-Helical-Cytolytic Peptide Assembling and Bioactive on Membrane Interface

Cytolytic peptides (CPs) have long been employed as broad-spectrum antibiotic agents to overcome multidrug resistance. However, the development of novel peptide drugs is still limited by the elusive molecular understanding of the membrane-lysis mechanism and modeling of CPs, especially of the short helical species. In this study, a known anticancer CP named PTP-7b (FLGALFKALSHLL) in disrupting membranes via self-assembling approach was studied by combining experiments and time-extended coarse-grained dynamic simulations. Effective membrane disintegration was induced by aggregation of the membrane-bound peptide individuals, rather than the preassembled peptide clusters. The disturbance level of lipid bilayers depended on the peptide concentrations, which was responsible for the long time-costing of PTP-7b in killing cells. On the basis of lines of simulations and energy-landscape calculations, the dynamics of membrane deformation evolving toward preliminary leakage resulted from the aggregated PTP-7b was demonstrated, which was subjected to the spatiotemporal cooperation of the membrane-inserted and the periplasmic peptides. The molecular mechanism incorporated the 11th histidine interaction coupled with the peptide amphiphilicity in accelerating phospholipid migration outward. This study revealed elaborate modeling and dynamics information about the short helical CPs in membrane lysis, which would be helpful to understand the underlying mechanisms and rational design of CPs for drug application.