Channel Crystal Structure and Antimicrobial Mechanism of Dermcidin from Human Skin

Abstract

Dermcidin is an anionic antimicrobial peptide (aAMP) derived from the human gene DCD, which encodes a preform that is secreted by eccrine sweat glands and subsequently proteolytically processed into DCD-1L, constituting a vital part of the innate host defense of the dermis. Recently its oligomeric structure was solved by x-ray crystallography and shown to be stabilized by divalent Zn2+ ions. Through molecular dynamics simulations, using a novel transmembrane conduction assay, we showed that it forms a conducting channel in a lipid bilayer. Long standing experimental results assign it a selective affinity for negatively charged membranes despite its anionic nature (pI ∼5), and in consensus with other amphiphilic AMPs it has a helical structure that only forms upon contact with a hydrophobic interface. The reconciliation of such experimental observations with the mechanistic result of channel formation pose further questions on the selectivity of dermcidin, both for anion conductivity and bacterial membrane adhesion, and for the kinetics of its insertion. Working to understand how the subunits of this channel-forming oligomer interact, we use molecular dynamics simulations to examine the influence and specific role of the Zn2+ ions for its stability under conditions relevant to understand it's selectivity for (and insertion into) specific composition lipid bilayers. In extension we examine the effect specific residue mutations which are based on a structure- and sequence-comparison to other known AMPs has for its function, as well as that of lipid bilayer composition.