Abstract
Solid-state NMR spectroscopic techniques provide valuable information about the structure, dynamics and topology of membrane-inserted polypeptides. In particular antimicrobial peptides (or ‘host defence peptides’) have early on been investigated by solid-state NMR spectroscopy and many technical innovations in this domain have been developed with the help of these compounds when reconstituted into oriented phospholipid bilayers. Using solid-state NMR spectroscopy it could be shown for the first time that magainins or derivatives thereof exhibit potent antimicrobial activities when their cationic amphipathic helix is oriented parallel to the bilayer surface, a configuration found in later years for many other linear cationic amphipathic peptides. In contrast transmembrane alignments or lipid-dependent tilt angles have been found for more hydrophobic sequences such as alamethicin or β-hairpin antimicrobials. This review presents various solid-state NMR approaches and develops the basic underlying concept how angular information can be obtained from oriented samples. It is demonstrated how this information is used to calculate structures and topologies of peptides in their native liquid-disordered phospholipid bilayer environment. Special emphasis is given to discuss which NMR parameters provide the most complementary information, the minimal number of restraints needed and the effect of motions on the analysis of the NMR spectra. Furthermore, recent 31P and 2H solid-state NMR measurements of lipids are presented including some unpublished data which aim at investigating the morphological and structural changes of oriented or non-oriented phospholipids. Finally the structural models that have been proposed for the mechanisms of action of these peptides will be presented and discussed in view of the solid-state NMR and other biophysical experiments.
Highlights
When the interactions of magainin 2 with phosphatidylcholine membranes have been studied isotropic signal intensities have been found to co-exists with bilayer structures, and at higher peptide-to-lipid ratios the membranes orient in the magnetic field, a behaviour that is similar to when detergent-phospholipid mixtures are prepared to form bicelles (Bechinger, 2005; Bechinger and Lohner, 2006)
The technique has the potential of a full-fledged structure determination of membrane-associated antimicrobial peptides (Bechinger et al, 1993; Cross, 1997) and has already revealed many important details that have allowed us to revise the initial models for their mechanism of action
The technique reveals many details which are important for the understanding of their functioning including aspects of conformational exchange, mosaicity and dynamics
Summary
In particular solid-state NMR spectroscopy provided the first indications for the alignment of linear cationic antimicrobial peptides parallel to the membrane surface thereby contrasting the models most common at the time which postulated the formation of transmembrane helical bundles (Bechinger et al, 1991; Bechinger et al, 1990).
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