Investigating the Therapeutic Ability of Novel Antimicrobial Peptide Dendropsophin 1 and Its Analogues through Membrane Disruption and Monomeric Pore Formation.

Abstract

Antimicrobial peptides (AMPs) are an alternative source of antibiotics that fight worldwide antibiotic-resistant catastrophes. Dendropsophin 1 (Dc1) is a recently invented novel AMP with 17 amino acid residues obtained from the screen secretion of a frog named Dendropsophus columbianus. Dc1 has two slightly mutated analogues, namely, Dc1.1 and Dc1.2, with improved cationicity and mean amphipathic moment to enhance the selective toxicity against microorganisms. Experimental results indicate that Dc1 and Dc1.1 have similar antimicrobial activity against Gram-negative bacteria Escherichia coli and Gram-positive bacteria Staphylococcus aureus, whereas the synthesized peptide Dc1.2 has shown antimicrobial activity against a wide range of microorganisms. However, the molecular level details of the peptide-membrane interaction and the corresponding changes in the peptide structure remain elusive. In this study, we investigate the bacterial membrane disruption capability of these AMPs by running a total of 14.2 μs long molecular dynamics (MD) simulations. Our findings suggest that all three peptides affect the upper layer of the membrane with different degrees of disruption. After penetration, Dc1 and Dc1.2 retain stable α-helices in the core region, indicating the potential to disrupt the second layer. However, secondary structure analysis shows that Dc1.2 attains extended helical regions on the C-terminus, suggesting it as the superior candidate among the analogues to have the potential of stable pore formation, leading to bacterial cell death. To speed up our study, we adopt a one-transmembrane configuration of Dc1, Dc1.1, and Dc1.2 and find toroidal pores with subsequent water leakage for Dc1.2.