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The action mechanism of human antimicrobial peptide dermcidin

Final Report Summary - AMDERM (The action mechanism of human antimicrobial peptide dermcidin)

The aim of the project is to study the action mechanism of the antimicrobial peptide ‘dermcidin’ (DCD). DCD is 48-amino acid peptide, secreted by human sweat glands and has broad-spectrum antimicrobial activities in human sweat. Since the discovery of the oligomeric structure of DCD, we have been trying to identify the detailed function mechanism of it. We revealed that the DCD oligomer forms uncontrollable ion channels on membranes, which will destroy the rest potential of cells, and eventually lead to cell death. Our ultimate goal is not only to reveal how DCD kills bacteria by interactions with the bacterial membrane, but also to understand why DCD can selectively do so against bacteria rather than human cells. Understanding the underlying mechanism of its function and selectivity perhaps would enable us to design and develop a new generation of antibiotics, which will alleviate the so-called ‘superbug’ crisis as more and more bacteria have developed multi-drug resistance.

In this project, we proposed to use multi-scale computer simulations, in collaboration with electrophysiology experiments, to study the effect of the composition of the membrane on the activity of DCD, as we suspect it is the membrane composition that determines the interaction with antimicrobial peptides. At the beginning of the object, we used coarse-grained (CG) molecular dynamics (MD) simulations to study the self-assembly process of the DCD oligomer with various lipid bilayers. We changed the lipid bilayer thicknesses and compositions (cholesterol abundance), and monitored the DCD oligomer orientation in these different bilayers in computer simulations. Interestingly, we found that the orientation of the DCD oligomer is systematically dependent on the thickness of the lipid bilayer in which it is inserted. To be brief, the DCD oligomer was found to be tilted when embedded into the lipid bilayer due to the hydrophobic mismatch, and the thinner the lipid bilayer, the larger the tilt angle. The presence of cholesterol effectively makes the bilayer thicker, and therefore leads to a smaller tilt angle of the DCD oligomer.

In the next stage, we utilized atomistic MD simulations, and the recently developed computational electrophysiology method, to study the relation between the DCD activity and its tilt angle when embedded in lipid bilayers. Since we have related the activity of DCD to its ion conductivity, we basically want to discover whether the tilt angle of the DCD oligomer has a significant impact on its ion conductivity. Through our extensive atomistic MD simulations using state-of-the-art computational methods and resources, we found a clear trend that when the DCD channel has a larger tilt angle in lipid bilayers, it usually exhibits a higher conductance, meaning it is more active. We attribute this to the unique ‘zigzag’ ion permeation pathway and existence of the side openings on the DCD oligomer.

In the meantime, we collaborated with our experimental colleagues, to work on electrophysiology experiments to measure the conductance of the DCD oligomer in simple bilayers with various percentage of cholesterol (0%, 20% and 40% proposed), to validate our findings in computer simulation studies. Unfortunately, after more than a year’s work, the experiment was not successful. Therefore, our simulation results have not been experimentally verified yet, but we will keep working on it.

In summary, we have used multi-scale computer simulations to study the effect of the membrane composition on the orientation and activity of the DCD oligomer, and obtained very interesting results: the thinner the membrane, the larger the tilt angle, the larger the conductance and therefore the more active the DCD peptide. These results have enriched our knowledge of the DCD function mechanism, and can potentially help to design and optimize DCD-based new antibiotics. That being said, experimental validation and further computational studies would be desired to reveal the whole story of the DCD action on various membranes, and more importantly, it selective function mechanisms against harmful bacteria.