Studies on the Interaction of Alyteserin 1c Peptide and Its Cationic Analogue with Model Membranes Imitating Mammalian and Bacterial Membranes

Abstract

Antimicrobial peptides (AMPs) are effector molecules of the innate immune system and have been isolated from multiple organisms. Their antimicrobial properties are due to the fact that they interact mainly with the anionic membrane of the microorganisms, permeabilizing it and releasing the cytoplasmic content. Alyteserin 1c (+2), an AMP isolated from Alytes obstetricans and its more cationic and hydrophilic analogue (+5) were synthesized using the solid phase method, in order to study the interaction with model membranes by calorimetric and spectroscopic assays. Differential scanning calorimetry (DSC) showed that both peptides had a strong effect when the membrane contained phosphatidylcholine (PC) alone or was mixed with phosphatidylglycerol (PG), increasing membrane fluidization. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) was used to study the secondary structure of the peptide. Peptide +2 exhibited a transition from β-sheet/turns to β-sheet/α-helix structures after binding with model membranes, whereas peptide +5 had a transition from aggregation/unordered to β-sheet/α-helix structures after binding with membrane-contained PC. Interestingly, the latter showed a β-sheet structure predominantly in the presence of PG lipids. Additionally, molecular dynamics (MD) results showed that the carboxy-terminal of the peptide +5 has the ability to insert into the surface of the PC/PG membranes, resulting in the increase of the membrane fluidity.

Increases in Hydrophilicity and Charge on the Polar Face of Alyteserin 1c Helix Change its Selectivity towards Gram-Positive Bacteria

“…Flexibility is an important property that affects antimicrobial activity, normally there is greater flexibility in the central region of the peptide that reflects a hinge, which facilitates contact with the apolar region of phospholipids and thus can be inserted into the membrane [37]. The flexibility in the peptides is affected by hydrophobic interactions and intermolecular hydrogen bonds that end up altering the functionality of the peptide, for example, the binding of the peptide with phospholipid can change the flexibility and also modify its conformation [11,38]. Therefore, to understand the dynamics of hydrogen bonds in these membrane systems, the interactions with residues 18-23 of both peptides were analyzed, showing a greater number of hydrogen bonds of these residues when interacting with POPE than with POPG.…”

“…Furthermore, the three-dimensional structure of Alyteserin-1c was characterized as an extended α-helix between Leu2 and Val21 residues [9]. In a recent study by Aragón-Muriel et al [11], it was reported that the Alyteserin-1c peptide and its more cationic and hydrophilic analog exhibited different secondary structures depending on the nature of the environment, including disordered structures and β-sheets.…”

“…For this reason, it is difficult to understand the mechanism of action of each peptide reported in the literature. In this context, in recent years, peptide-membrane studies using molecular dynamics have helped to overcome this bottleneck and to understand the mechanism of action of several antimicrobial peptides [11][12][13][14], due to the detailed information, accuracy of the results, and reductions of study time and cost.…”

In Vitro Evaluation of the Potential Pharmacological Activity and Molecular Targets of New Benzimidazole-Based Schiff Base Metal Complexes

“…After the addition of ligands and complexes to both lipid systems at a 1:50 compound:lipid molar ratio, the pre-transition peak was completely abolished, suggesting that both free ligands and metal-bound complexes have the ability to disrupt the organization of membranes [ 48 ]. In multilamellar vesicles (MLVs) made up of DMPC lipids, the Tm was modestly reduced after ligands and complexes were added, shifting the main transition peaks to the left ( Figure 3 ) and suggesting that the compounds may increase the fluidity of the membrane in response to the alteration of the hydrophobic bilayer core.…”

Antimicrobial Contribution of Chitosan Surface-Modified Nanoliposomes Combined with Colistin against Sensitive and Colistin-Resistant Clinical Pseudomonas aeruginosa

“…Molecular dynamics simulations provide valuable and reliable information about the interaction of peptides with membrane models [18,19], which is useful to understand the behavior of CST in relation to liposomal systems. An advantage of using micelles as opposed to lipid bilayers is the faster time scales of motion of dodecylphosphocholine (DPC) lipids [20].…”