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. 2021 Jan 12;22(2):691.
doi: 10.3390/ijms22020691.

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

Francisco Ramos-Martín  1 , Nicola D'Amelio  1
Affiliations

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

Francisco Ramos-Martín et al. Int J Mol Sci. .

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.

Keywords: antibiotic resistance; anticancer; antimicrobial peptide; biophysics; esophageal carcinoma; molecular dynamics; sequence alignment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
(A) Sequence logo calculated from cecropinXJ (CXJ) sequence-related (SR) family; (B) members of CXJ SR family; (C) Define secondary structure of proteins (DSSP)-based secondary structure for each member of CXJ SR family.
Figure 2
Figure 2
(A) Helical wheel plot (generated with NetWheels [50]); (B) I-TASSER structural prediction of CXJ. The peptide backbone is colored from blue (N-terminus) to red (C-terminus). Side chains are shown as sticks with the following color code: positively charged (blue), negatively charged (red), non-polar (light gray), polar (yellow). Residues separating the two helices are labeled; (C) DSSP secondary structures calculated along molecular dynamics (MD) simulation of CXJ in solution.
Figure 3
Figure 3
MD snapshots representative of CXJ peptide interacting with several membranes of variable phospholipid compositions. (A) 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC); (B) POPC/cholesterol (CHO); (C) POPC/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS)/CHO; (D) POPC/POPS; (E) POPS; (F) 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE); (G) 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (POPG); (H) PE/PG, (I) PE/PG/cardiolipin (CL); (J) CL; (K) 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoinositol (POPI); (L) PE/ergosterol (ERGO). Color code: phosphorus atom: yellow, POPC black (body) and light gray (choline group), POPS brown (body), gold (headgroup), light yellow (amine of the headgroup) and orange (carboxyl of the headgroup), POPE dark green (body), turquoise (headgroup), light green (amine of the headgroup), POPG dark violet (body), violet (headgroup), light violet (hydroxyls of the headgroup), POPI blue (body), light blue (headgroup), cyan (hydroxyls of the headgroup); CL dark red (body) and light red (headgroup), ERGO dark orange (body) and light orange (hydroxyl); CHO purple (body) and light purple (hydroxyl). Panel (B–D,H,I,L) show lipid composition modeling mammal cells (B), cancer cells (C,D), bacteria (H,I) and fungal cells (L). For clarity, only functional groups of headgroups are shown (spheres) in the upper leaflet. CXJ peptide is shown as a “tube” colored from blue (N-terminus) to red (C-terminus). Side chains are shown as sticks with the following color code: positively charged (blue), negatively charged (red), non-polar (light gray), polar (yellow).
Figure 4
Figure 4
Contact maps showing how each residue of CXJ interacts with others in presence of different membranes: (A) POPC; (B) POPC/POPS/CHO; (C) POPE; (D) POPE/POPG; (E) POPE/POPG/CL; (F) POPE/ERGO.
Figure 5
Figure 5
Occurrence of polar atom contacts (H-bonds and salt bridges) between CXJ peptide and various membrane bilayers calculated along MD simulation trajectories: (A) POPC/POPS/CHO; (B) POPE; (C) POPE/POPG; (D) POPE/POPG/CL. TOCL2 refers to CL.
Figure 6
Figure 6
Occurrence of van der Waals contacts between CXJ peptide and various membrane bilayers calculated along MD simulation trajectories: (A) POPC/POPS/CHO; (B) POPE; (C) POPE/POPG; (D) POPE/POPG/CL. TOCL2 refers to CL.
Figure 7
Figure 7
Order parameter of C-H moieties of palmitoyl side chains in membranes containing various phospholipids compositions as calculated from multiple repetitions of MD simulations in the absence (2 repetitions in black labeled as 1 and 2) and in the presence (3 repetitions in red labeled from 1 to 3) of eight CXJ peptides. (A) example snapshot of one simulation with eight peptides (color code in the caption of Figure 3); (B) POPC/CHO, (C), POPC/POPS/CHO, (D) POPC/POPS, (E) POPS, (F) POPE; (G) POPG; (H) POPE/POPG; (I) POPE/POPG/TOCL2; (J) TOCL2; (K) POPI; (L) POPE/ERGO. TOCL2 refers to CL.
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