Membrane-Binding and Aggregation Thermodynamics Explain the Mechanism and Selectivity of Antimicrobial Lipopeptides: Results from Molecular Simulation

The emergence of antibiotic-resistant pathogens is one of the major health challenges of the 21st century, igniting significant interest in novel compounds based on antimicrobial peptides; these peptides kill bacteria by attacking and damaging their cell membranes. Despite their initial promise, natural antimicrobial peptides have not been particularly successful as drug candidates, due to issues with synthesis and bioavailability. Here we explore the physical properties of synthetic lipopeptides designed to overcome these limitations. Combining coarse-grained molecular dynamics and free energy calculations using a novel contact-based reaction coordinate, we examine the thermodynamics of the membrane binding, focusing on the role of lipid composition, lipopeptide aggregation state, and salt concentration. The results demonstrate the crucial role played by lipopeptide aggregation in controlling their function and selectivity for their target membranes. These new insights will help us rationally improve the design of new antimicrobials.