Concentration-Dependent Membrane Interactions and Pore Stability of Aurein 1.2 and LLAA Revealed by Coarse-Grained Molecular Dynamics Simulations

Context Aurein 1.2 is a short cationic antimicrobial peptide secreted by the Australian tree frog Litoria aurea. In this study, we investigated the concentration-dependent interactions of aurein 1.2 and its analogue LLAA with model membranes representing bacterial and eukaryotic lipid bilayers. LLAA exhibited stronger membrane interactions and deeper insertion than aurein, particularly in bacterial membranes. The simulations further showed that peptide separation from aggregates facilitates membrane insertion. In pre-formed pore systems, LLAA pores rapidly disassembled whereas aurein pores remained stable for substantially longer times, especially in bacterial membrane models. These findings demonstrate how subtle differences in peptide sequence and charge distribution influence membrane insertion, peptide organization, and pore stability. Methods Coarse-grained molecular dynamics simulations were performed using the MARTINI force field with the polarizable water model. Simulations were carried out with GROMACS for systems containing single peptides, multiple peptides, and pre-formed pores in POPC, DPPC, and POPE/POPG bilayers. Peptide insertion, electrostatic interactions, pore stability, and water permeation were analyzed using GROMACS analysis tools together with custom VMD Tcl and C++ scripts.