Interaction of Antimicrobial Lipopeptides with Bacterial Lipid Bilayers

Abstract

The resistance of pathogens to traditional antibiotics is currently a global issue of enormous concern. As the discovery and development of new antibiotics become increasingly challenging, synthetic antimicrobial lipopeptides (AMLPs) are now receiving renewed attention as a new class of antimicrobial agents. In contrast to traditional antibiotics, AMLPs act by physically disrupting the cell membrane (rather than targeting specific proteins), thus reducing the risk of inducing bacterial resistance. In this study, we use microsecond-timescale atomistic molecular dynamics simulations to quantify the interaction of a short AMLP (C16-KKK) with model bacterial lipid bilayers. In particular, we investigate how fundamental transmembrane properties change in relation to a range of lipopeptide concentrations. A number of structural, mechanical, and dynamical features are found to be significantly altered in a non-linear fashion. At 10 mol% concentration, lipopeptides have a condensing effect on bacterial bilayers, characterized by a decrease in the area per lipid and an increase in the bilayer order. Higher AMLP concentrations of 25 and 40 mol% destabilize the membrane by disrupting the bilayer core structure, inducing membrane thinning and water leakage. Important transmembrane properties such as the lateral pressure and dipole potential profiles are also affected. Potential implications on membrane function and associated proteins are discussed.

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

“…Figure S8 shows a rigidification clearly visible for PG and PS membranes, as expected. The increase of order observed upon peptide binding is not so uncommon, and depends on factors like lipid composition of the membrane, temperature, and charge [ 58 , 60 , 87 , 88 , 89 ]. Sometimes, peptides that attach to the surface of the bilayer can increase acyl chain packing [ 90 , 91 ], especially when a strong electrostatic attraction is established [ 91 ].…”

“…The rigidification effect upon binding is also consistent with the observed hydrophobic thickness ( Figure S9 ), that greatly increases for POPG, POPG containing membranes and CL as compared to POPC. Furthermore, the observed decrease in the electron density ( Figure S9 ) can be a consequence of more water molecules being located near the polar head groups due to more loosely packaging caused by the presence of the peptides [ 88 , 92 , 93 ].…”

Design, Screening, and Testing of Non-Rational Peptide Libraries with Antimicrobial Activity: In Silico and Experimental Approaches

“…Their results demonstrated that POPE phospholipids have a higher diffusion coefficient than POPG. Additionally, it was found that there is a strong correlation between the choice of FFs and the simulation conditions with the calculated values for the lateral diffusion coefficients [200].…”

The Effect of Lipid Composition on the Dynamics of Tau Fibrils

“…The order parameters of the pure POPE lipids match with the earlier simulation and experimental results. [37][38][39] The decrease in the order parameter is observed in both sn-1 and sn-2 chains. The decreasing S CD order parameter…”