Influence of Lipid Composition on the Orientational State of the Antimicrobial Peptide MSI-103 in Membranes. a Solid-State NMR Study

Abstract

The antimicrobial peptide MSI-103 is known to undergo a functionally relevant re-orientation in membranes from a surface-aligned S-state to a tilted T-state depending on the peptide concentration and lipid phase. Here, we have used solid-state NMR on the 2H-labeled peptide to determine its orientational state in membranes composed of different types of lipids.In phosphatidylcholine (PC) bilayers with different acyl chains, there is no effect of the chain length on the peptide orientation. However, a distinct difference is observed in the peptide response to saturated and unsaturated acyl chains. In unsaturated lipids, the peptide always remains in the surface-bound S-state, with its alpha-helical axis perpendicular to the bilayer normal at a tilt angle close to 90°. Only in saturated lipids it is able to insert into the membrane in a tilted T-state, with an angle of around 125°. Interestingly, when lyso-PC is added, the T-state is found to be stable also in unsaturated lipids. These results can be explained by the shape of the lipids; especially the relative area of head group and acyl chains, as will be discussed in detail. It is known that the presence of anionic lipids leads to a higher affinity of the cationic peptide towards bacterial membranes, but such electrostatic effects per se do not suffice to induce any change in peptide orientation. Interestingly, we found that the presence of cholesterol prevents MSI-103 from binding to the membrane in any ordered state, but rather induces the formation of immobilized peptide aggregates. This observation can essentially explain the selective membrane-permeabilizing action of MSI-103 on bacteria compared to eukaryotic cells which contain cholesterol.