Self-assembly and interactions of short antimicrobial cationic lipopeptides with membrane lipids: ITC, FTIR and molecular dynamics studies

Abstract

In this work, the self-organization and the behavior of the surfactant-like peptides in the presence of biological membrane models were studied. The studies were focused on synthetic palmitic acid-containing lipopeptides, C16-KK-NH2 (I), C16-KGK-NH2 (II) and C16-KKKK-NH2 (III). The self-assembly was explored by molecular dynamics simulations using a coarse-grained force field. The critical micellar concentration was estimated by the surface tension measurements. The thermodynamics of the peptides binding to the anionic and zwitterionic lipids were established using isothermal titration calorimetry (ITC). The influence of the peptides on the lipid acyl chain ordering was determined using FTIR spectroscopy. The compounds studied show surface-active properties with a distinct CMC over the millimolar range. An increase in the steric and electrostatic repulsion between polar head groups shifts the CMC toward higher values and reduces the aggregation number. An analysis of the peptide-membrane binding revealed a unique interplay between the initial electrostatic and the subsequent hydrophobic interactions enabling the lipopeptides to interact with the lipid bilayer. In the case of C16-KKKK-NH2 (III), compensation of the electrostatic and hydrophobic interactions upon binding to the anionic membrane has been suggested and consequently no overall binding effects were noticed in ITC thermograms and FTIR spectra.

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…These models are simplistic and, consequently, they have some limitations, and it is necessary to evaluate whether the selected model fits the purpose of the simulation [86]. However, these models have been used to evaluate drug-membrane interactions, such as volatile anaesthetics [89], antiparasitic drugs [90] and antimicrobial peptides [91][92][93][94][95][96][97][98]. Bereau and Kremer (2015) showed that MD simulations with coarse-grained models can lead to free energy profiles that are similar to those obtained by allatom simulations [99].…”

pVEC hydrophobic N‐terminus is critical for antibacterial activity

“…The uptake and membrane interaction mechanisms of some CPPs and AMPs have been examined using experimental methods for accurate representation of cellular environments and computational methods for atomistic details, but a clear description is still missing for pVEC . Peptide translocation takes place on the order of minutes, and in addition, the cellular and membrane environment is more complex than a simple membrane model.…”

“…Lys11 in the pVEC sequence are highly conserved in VE-cadherin proteins from different organisms, suggesting that they carry functional importance for the full-length protein as well. 38 The uptake and membrane interaction mechanisms of some CPPs and AMPs have been examined using experimental methods for accurate representation of cellular environments 29,[39][40][41][42] and computational methods [43][44][45][46] for atomistic details, but a clear description is still missing for pVEC. 3 Peptide translocation takes place on the order of minutes, 47,48 and in addition, the cellular and membrane environment is more complex than a simple membrane model.…”

Membrane Active Peptides and Their Biophysical Characterization

“…hydrogen, van der Waals) that drive the process forward [273,274]. Computational approaches can further give an insight to the initial electrostatic interactions that govern the binding of lipopeptides to the hydrophobic core of the membrane [275]. The atomistic level of detail afforded by simulations opens the path toward the design of novel peptide analogs with increased efficacy [276].…”