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1.B.161. The Pore-forming Short-chain Synthetic beta-Peptide (PSSP) Family 

Amphiphilic beta-peptides, which are synthetically designed short-chain helical foldamers of beta-amino acids, are established potent biomimetic alternatives of natural antimicrobial peptides. An intriguing question is: how does the distinct molecular architecture of these short-chain and rigid synthetic peptides translates to its potent membrane disruption ability? Koneru et al. 2021 address this question via a combination of all atom and coarse-grained molecular dynamics simulations of the interaction of a mixed phospholipid bilayer with an antimicrobial 10-residue globally amphiphilic helical beta-peptide at wide range of concentrations. The simulation demonstrates that multiple copies of this synthetic peptide, initially placed in aqueous solution, readily self-assemble and adsorb at membrane interface. Subsequently, beyond a threshold peptide-to-lipid ratio, the surface-adsorbed oligomeric aggregate moves inside the membrane and spontaneously forms stable water-filled transmembrane pores via a cooperative mechanism. The defects induced by these pores lead to the dislocation of interfacial lipid head groups, membrane thinning and substantial water leakage inside the hydrophobic core of the membrane. A molecular analysis revealed that, despite having a short architecture, these synthetic peptides, once inside the membrane, stretch towards the distal leaflet in favour of potential contact with polar head groups and the interfacial water layer. The pore formed in coarse-grained simulation was found to be resilient upon structural refinement, and the pore-inducing ability was found to be elusive in a non-globally amphiphilic sequence isomer of the same beta-peptide, indicating strong sequence dependence (Koneru et al. 2021). 

References associated with 1.B.161 family:

Koneru, J.K., D.D. Prakashchand, N. Dube, P. Ghosh, and J. Mondal. (2021). Spontaneous Transmembrane Pore Formation by Short-chain Synthetic Peptide. Biophys. J. [Epub: Ahead of Print] 34478698