Deciphering How Pore Formation Causes Strain-Induced Membrane Lysis of Lipid Vesicles

Abstract

Pore formation by membrane-active antimicrobial peptides is a classic strategy of pathogen inactivation through disruption of membrane biochemical gradients. It remains unknown why some membrane-active peptides also inhibit enveloped viruses, which do not depend on biochemical gradients. Here, we employ a label-free biosensing approach based on simultaneous quartz crystal microbalance-dissipation and ellipsometry measurements in order to investigate how a pore-forming, virucidal peptide destabilizes lipid vesicles in a surface-based experimental configuration. A key advantage of the approach is that it enables direct kinetic measurement of the surface-bound peptide-to-lipid (P:L) ratio. Comprehensive experiments involving different bulk peptide concentrations and biologically relevant membrane compositions support a unified model that membrane lysis occurs at or above a critical P:L ratio, which is at least several-fold greater than the value corresponding to the onset of pore formation. That is consistent with peptide-induced pores causing additional membrane strain that leads to lysis of highly curved membranes. Collectively, the work presents a new model that describes how peptide-induced pores may destabilize lipid membranes through a membrane strain-related lytic process, and this knowledge has important implications for the design and application of membrane-active peptides.

Targeting vesicle size

“…1b, bottom). In contrast, liposomes of > 160 nm have low membrane curvatures that are not susceptible to AH peptide-mediated pore formation, thus no lysis occurs 5 . In agreement with the liposome results, tested viruses prone to AH peptide inhibition fall within the disruptive range of liposome size: flaviviruses, 40-60 nm; chikungunya virus, 60-70 nm; bunyaviruses, 90-100 nm; and human immunodeficiency virus, 120 nm.…”

An enzymatic assay based on luciferase Ebola virus-like particles for evaluation of virolytic activity of antimicrobial peptides

“…However, the proposed mechanism does not explain virolytic properties of peptides because enveloped viruses do not depend on biochemical gradients. Jackman et al [29] propose that the lysis of the viral membrane is strain induced. The membrane enveloping the virus core is highly curved imposing substantial stress.…”

Materials Nanoarchitectonics for Mechanical Tools in Chemical and Biological Sensing

“…Kinetic analysis of the QCM‐D measurement data indicated that cooperative peptide binding leads to pore formation and vesicle rupture, whereas noncooperative binding does not cause vesicle rupture. Combined measurement approaches involving QCM‐D and ellipsometry experiments have further identified that a critical density of peptide‐induced pores form in a lipid vesicle before rupture occurs . Figure illustrates the experimental strategy to measure the peptide (P)/lipid (L) ratio.…”

“…Combined measurement approaches involving QCM-D and ellipsometrye xperiments have further identified that ac riticald ensity of peptide-induced pores form in al ipid vesicle before ruptureo ccurs. [62] Figure 7i llustrates the experimental strategy to measuret he peptide( P)/lipid (L) ratio. In particular,alipid-based model system composed of substrate-supported adsorbed vesicles was monitored by using simultaneousQCM-D and ellipsometry measurements to investigate the membrane-peptide interaction.…”

“…These measurementswere applied to evaluate the AH peptide's potential as an antiviral drug candidate.R eprinted with permission from Ref. [62].Copyright 2016 American Chemical Society.…”