Abstract
The cathelicidin derived bovine antimicrobial peptide BMAP27 exhibits an effective microbicidal activity and moderate cytotoxicity towards erythrocytes. Irrespective of its therapeutic and multidimensional potentiality, the structural studies are still elusive. Moreover, the mechanism of BMAP27 mediated pore formation in heterogeneous lipid membrane systems is poorly explored. Here, we studied the effect of BMAP27 in model cell-membrane systems such as zwitterionic, anionic, thymocytes-like (TLM) and leukemia-like membranes (LLM) by performing molecular dynamics (MD) simulation longer than 100 μs. All-atom MD studies revealed a stable helical conformation in the presence of anionic lipids, however, significant loss of helicity was identified in TLM and zwitterionic systems. A peptide tilt (~45˚) and central kink (at residue F10) was found in anionic and LLM models, respectively, with an average membrane penetration of < 0.5 nm. Coarse-grained (CG) MD analysis on a multi-μs scale shed light on the membrane-dependent peptide and lipid organization. Stable micelle and end-to-end like oligomers were formed in zwitterionic and TLM models, respectively. In contrast, unstable oligomer formation and monomeric BMAP27 penetration were observed in anionic and LLM systems with selective anionic lipid aggregation (in LLM). Peptide penetration up to ~1.5 nm was observed in CG-MD systems with the BMAP27 C-terminal oriented towards the bilayer core. Structural inspection suggested membrane penetration by micelle/end-to-end like peptide oligomers (carpet-model like) in the zwitterionic/TLM systems, and transmembrane-mode (toroidal-pore like) in the anionic/LLM systems, respectively. Structural insights and energetic interpretation in BMAP27 mutant highlighted the role of F10 and hydrophobic residues in mediating a membrane-specific peptide interaction. Free energy profiling showed a favorable (-4.58 kcal mol-1 for LLM) and unfavorable (+0.17 kcal mol-1 for TLM) peptide insertion in anionic and neutral systems, respectively. This determination can be exploited to regulate cell-specific BMAP27 cytotoxicity for the development of potential drugs and antibiotics.
Highlights
Small cationic peptides that possess cell penetrating ability are a component of natural immune systems and comprise a large family of immune-defense molecules found in most living organisms [1, 2]
Its helical conformation was studied by circular dichroism (CD) and solution nuclear magnetic resonance (NMR) techniques [9, 12]
Truncation of the hydrophobic C-terminal end has been shown to cause a significant decrease in the peptide cytotoxicity to human erythrocytes and neutrophils, while conserving their microbicidal activity [9, 11, 12]
Summary
Small cationic peptides that possess cell penetrating ability are a component of natural immune systems and comprise a large family of immune-defense molecules found in most living organisms [1, 2]. The antimicrobial and anticancer activities are mediated by a series of steps that include peptide attraction to the membrane, binding, distribution/aggregation, reorientation and insertion followed by cell lysis [3]. These peptides have cationic and hydrophobic amino acid residues and assume variable secondary structures such as α-helix or β-strands with disulfide bonds or extended conformation [4, 5]. BMAP27 is moderately cytotoxic to human neutrophils and erythrocytes [12] Their depolarization potentiality at the inner mitochondrial membrane followed by cell death suggests its membrane permeability [11]. The structures in bovine cathelicidins have not been studied so far
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