Structural studies of antimicrobial peptides provide insight into their mechanisms of action.

Abstract

AbstractThis chapter reviews structural studies of antimicrobial peptides (AMPs), with a focus on human defensins and cathelicidins. Also discussed are the major steps for structural determination of AMPs by nuclear magnetic resonance spectroscopy, including bacterial expression and purification, sample preparations, data collection, sequential signal assignments, structure calculations, validation and coordinate deposition. A variety of three-dimensional structures (α-helices, β-strands, αβ-fold and non-αβ structures) have been discovered for AMPs, which can induce similar biophysical consequences in membranes such as positive curvature or lipid domain formation. Therefore, it is the amphipathic surface, not polypeptide backbone scaffolds, that is essential for the antimicrobial activity of AMPs. A proper presentation of side chains (e.g. cationic and hydrophobic) on the surface of AMPs determines not only membrane perturbation potential, but also other biological functions. Reduction in hydrophobicity is a fundamental strategy to improve peptide selectivity. Structures of AMPs in complex with membranes or non-membrane targets also form the foundation for engineering a new generation of antimicrobials that will supplement or replace traditional resistant antibiotics.