Membrane Active Peptides and Their Biophysical Characterization

Abstract

In the last 20 years, an increasing number of studies have been reported on membrane active peptides, which exert their biological activity by interacting with the cell membrane either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. These peptides are attractive alternatives to currently used pharmaceuticals. Antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery currently in the drug pipeline suggest that these membrane active peptides will soon constitute a significant percentage of the drug market. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). AMPs are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus and fungi. CPPs are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity to some extent. Biophysical techniques to understand how they interact with the membrane have shed light on the peptide-membrane interaction at various levels of detail. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Advances in live imaging techniques have allowed examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provided clues on the peptide-lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC.

Molecular Basis of the Anticancer and Antibacterial Properties of CecropinXJ Peptide: An In Silico Study

“…MD simulations and modeling of membrane permeabilization rely on the assumption that permeabilization is an equilibrium process, a condition that is not always fulfilled, especially in the case of stochastic permeabilization [ 122 , 123 , 124 ]. The detection of such long processes [ 129 , 130 ] would require more advanced sampling algorithms including dual-resolution MD [ 131 ], coarse-grain simulations, steered MD [ 132 ], umbrella-sampling [ 133 , 134 ], metadynamics [ 135 , 136 ] or replica exchange, among others [ 130 , 137 , 138 , 139 ]. Our aim is to characterize the first steps of the interaction that are stationary on shorter timescales.…”

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

“…Our slow exchange conditions therefore limit the value of k ex and k off to a maximum of 600 s −1 and the lifetime of the complex to a minimum of 1.7 milliseconds or much more, including the case of irreversible binding (the lifetime is the inverse of the off-rate constant). The detection of such long processes [ 74 , 75 ] would require more advanced sampling algorithms including dual-resolution MD [ 76 ], coarse-grain simulations, steered MD [ 77 ], umbrella-sampling [ 78 , 79 ], metadynamics [ 80 , 81 ], or replica exchange, among others [ 75 , 82 , 83 ]. This is beyond the scope of this work that aims at characterizing the steps at the very beginning of the interaction, in order to unravel the mode of action.…”

Investigating the interactions of the first 17 amino acid residues of Huntingtin with lipid vesicles using mass spectrometry and molecular dynamics

“…Peptides that interact with the plasma membrane through processes of traversal, fusion, or residing directly at the membrane surface interface are termed membrane active . It has been suggested that the manner in which the peptide locates within the membrane is highly dependent on the membrane lipid composition .…”

“…It has been suggested that the manner in which the peptide locates within the membrane is highly dependent on the membrane lipid composition . Broadly categorized, the interactions have been described as the “barrel‐stave” and “carpet” mechanisms . The former process involves the insertion of the peptide into the membrane core while the latter involves binding at the surface primarily through interactions with the polar head groups.…”