Structural Biology of Antimicrobial Peptides by NMR Spectroscopy
Antimicrobial peptides are key components of innate immunity of all life forms. Understanding the structureactivity relationship of these peptides is essential for developing them into novel therapeutics that substitutes traditional antibiotics. NMR spectroscopy can provide insights into membrane-targeting antimicrobial peptides from a variety of angles. First, three-dimensional structures of antimicrobial peptides can be determined by solution NMR using short-chain phosphatidylglycerol micelles as a novel bacterial membrane-mimetic model. Natural abundance 15N and 13C chemical shifts of short peptides offer a practical approach for the refinement of distance-based structures. Isotope labeling will allow structures of antimicrobial peptides with longer or difficult sequences to be determined in lipid micelles or bicelles and further refined by residual dipolar couplings. The in-plane or transmembrane orientation of antimicrobial peptides in lipid bilayers can be determined by solid-state NMR. Second, the impact of antimicrobial peptides on the structure and dynamics of lipid bilayers can be probed by 31P and 2H NMR spectroscopy. Third, intermolecular nuclear Overhauser effects (NOE) provide direct evidence for the location of the peptides in the membranes and are key restraints for establishing the structure of peptide-lipid complexes. Peptide-lipid NOE patterns also reflect the penetration depth of peptides in membranes. A deeper penetration is required for a basic peptide to exert its membrane perturbation potential on acidic membranes. The combination of solution and solid-state NMR depicts a more complete picture how antimicrobial peptides perturb bacterial membranes. The membrane-bound structures of antimicrobial peptides can be harnessed to guide peptide engineering to improve the therapeutic index.
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Document Type: Research Article
Affiliations: Eppley Institute, Room ECI3018, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.
Publication date: 01 March 2006