The effect of acidic pH on the adsorption and lytic activity of the peptides Polybia-MP1 and its histidine-containing analog in anionic lipid membrane: a biophysical study by molecular dynamics and spectroscopy

Abstract

Antimicrobial peptides (AMPs) are part of the innate immune system of many species and are compounds with potential application against the development of resistant bacterial strains promoted by conventional antibiotics. The AMPs are rich in cationic and hydrophobic residues and act directly on the lipidic phase of the cell membranes. The MP1 has a broad-spectrum bactericide activity in both Gram-negative and positive bacteria, not being hemolytic or cytotoxic. H-MP1 is a synthetic analog of MP1 with lysines replaced by histidines so that its net charge could be responsive to changes in solution pH. In the present work, we investigated the effect of the solution pH on the structural properties, in the adsorption and insertion, and on the lytic activity of these peptides in lipid bilayers mimicking the cell membrane of Gram-negative bacteria, using experimental and computational biophysical techniques. The results indicate that the lytic activity of H-MP1 is sensitive to pH, increasing to an acidic environment, matching that of MP1, which is not influenced by solution pH. Molecular Dynamic simulations indicated that the adsorption process of both peptides started by the interaction of the N-terminus with the bilayer, followed by preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

One New Acid-Activated Hybrid Anticancer Peptide by Coupling with a Desirable pH-Sensitive Anionic Partner Peptide

“…Ingeniously masking positive charges of ACPs is a promising strategy to enhance selectivity and reduce toxicity . Some acid-activated anticancer peptides or recombinant peptides have been developed using the protonation of histidine in an acidic environment, like substituting lysines/arginines for histidines or fusing with specific binding peptides. − ,, Previously, we have also obtained a series of pH-responsive anticancer peptides by histidine substitutions and introduction of anionic binding peptides based on the short cationic α-helical ACP LK. , In addition, we found that the coupling of anionic binding peptides to cationic LK could play a major role in improving peptide stability. Thus, the anionic peptide fusion strategy might be a good approach to obtain the pH selectivity concomitant with enhancing the stability of ACPs.…”

“…31 Some acid-activated anticancer peptides or recombinant peptides have been developed using the protonation of histidine in an acidic environment, like substituting lysines/ arginines for histidines or fusing with specific binding peptides. [32][33][34]38,39 Previously, we have also obtained a series of pH-responsive anticancer peptides by histidine substitutions and introduction of anionic binding peptides based on the short cationic α-helical ACP LK. 36,37 In addition, we found that the coupling of anionic binding peptides to cationic LK could play a major role in improving peptide stability.…”

Probing Mastoparan-like Antimicrobial Peptides Interaction with Model Membrane Through Energy Landscape Analysis

“…Experimental findings have shown that, in an acidic environment, MP1 presents an affinity to the membrane 1.5 times higher than H-MP1. 11 In addition, H-MP1 has a shallower insertion and about three times less lytic activity than MP1. 11 Details on how charge distribution, size of charged side chains, and secondary structure of AMPs affect the binding to the membrane remain unclear, 56−58 although the α-helix structure of AMPs might be important to decrease toxicity.…”

“…Its adsorption to the bacterial membrane is followed by their α-helix structuring, modulated by electrostatic and hydrophobic interactions. After adsorption, according to the orientation of the peptides, changes in several physical properties of the membrane can be observed, such as thickness, decrease in the order parameter of the acyl chains, and alterations of membrane phase behavior. , …”

Multiple roles of ribosomal antimicrobial peptides in tackling global antimicrobial resistance

“…Several AMP families have been reported to possess various secondary structures. For example, cecropins [47], lasioglossins [48], melittin [49] and Polybia-MP1 [50][51][52] form α-helical regions. Insect defensins form β-sheet conformations or proline/glycine-rich peptides [53], for example, drosocin [54], lebocins and attacin [55] show extended structures.…”