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

Abstract

Esophageal cancer is an aggressive lethal malignancy causing thousands of deaths every year. While current treatments have poor outcomes, cecropinXJ (CXJ) is one of the very few peptides with demonstrated in vivo activity. The great interest in CXJ stems from its low toxicity and additional activity against most ESKAPE bacteria and fungi. Here, we present the first study of its mechanism of action based on molecular dynamics (MD) simulations and sequence-property alignment. Although unstructured in solution, predictions highlight the presence of two helices separated by a flexible hinge containing P24 and stabilized by the interaction of W2 with target biomembranes: an amphipathic helix-I and a poorly structured helix-II. Both MD and sequence-property alignment point to the important role of helix I in both the activity and the interaction with biomembranes. MD reveals that CXJ interacts mainly with phosphatidylserine (PS) but also with phosphatidylethanolamine (PE) headgroups, both found in the outer leaflet of cancer cells, while salt bridges with phosphate moieties are prevalent in bacterial biomimetic membranes composed of PE, phosphatidylglycerol (PG) and cardiolipin (CL). The antibacterial activity of CXJ might also explain its interaction with mitochondria, whose phospholipid composition recalls that of bacteria and its capability to induce apoptosis in cancer cells.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Molecular dynamics simulations are frequently used to provide information regarding (1) peptide conformation (e.g., % of helicity) [786][787][788][789][790][791][792][793][794][795][796][797][798], (2) peptide location (at the membrane interface or inserted into the bilayer core), and (3) orientation in the membrane [783,[787][788][789][790][792][793][794]796,[799][800][801][802][803][804][805][806]. As we stated previously, simulations can also provide information regarding the effects of the peptides on membrane properties, including (1) the extent of ordering in the acyl tails, (2) the overall membrane thickness, and (3) curvature [793,794,799,800,807] as well as the formation of membrane defects [794].…”

“…As we stated previously, simulations can also provide information regarding the effects of the peptides on membrane properties, including (1) the extent of ordering in the acyl tails, (2) the overall membrane thickness, and (3) curvature [793,794,799,800,807] as well as the formation of membrane defects [794]. MD simulations and other computational methods, combined with complementary experimental methods, can be used to design more effective antimicrobial [783,798,[808][809][810][811] and anticancer peptides [747,789,[812][813][814]. For designing new peptides, an understanding of the interactions between peptides and lipids is of particular interest.…”

Lipid saturation and head group composition have a pronounced influence on the membrane insertion equilibrium of amphipathic helical polypeptides

“…The in-plane topology is probably stabilized by the negative surface charge density and the additional hydrogen bonding possibilities of the PG bilayers that favorably interact with the histidines (and lysines). Indeed, molecular dynamics calculations show an accumulation of close contacts between cationic amino acids of membrane-inserted antimicrobial peptides and the PG phosphate groups [64,65]. Furthermore, due to the negative surface charge density of the PG bilayer there is a pH gradient between the bulk and the membrane surface during the sample preparation which may persist even in the reduced volume of the stacked membranes (Fig.…”

Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics

“…Specifically, cecropin XJ can cause apoptosis and inhibit cancer cell proliferation through the mitochondrial apoptosis pathways [154]. Moreover, cecropin XJ targets phosphatidylserine and phosphatidylethanolamine, both found in cancer cells' outer membrane, and targets phosphatidylglycerol and cardiolipin, which explains its interactions with the mitochondria during apoptosis [155].…”