In Search of a Molecular View of Peptide-Lipid Interactions in Membranes

Lipidbilayer membranes are often represented as a continuous nonpolarslab with a certain thickness bounded by two more polar interfaces.Phenomena such as peptide binding to the membrane surface, folding,insertion, translocation, and diffusion are typically interpretedon the basis of this view. In this Perspective, I argue that thismembrane representation as a hydrophobic continuum solvent is notadequate to understand peptide-lipid interactions. Lipids arenot small compared to membrane-active peptides: their sizes are similar.Therefore, peptide diffusion needs to be understood in terms of freevolume, not classical continuum mechanics; peptide solubility or partitioningin membranes cannot be interpreted in terms of hydrophobic mismatchbetween membrane thickness and peptide length; peptide folding andtranslocation, often involving cationic peptides, can only be understoodif realizing that lipids adapt to the presence of peptides and themembrane may undergo considerable lipid redistribution in the process.In all of those instances, the detailed molecular interactions betweenthe peptide residues and the lipid components are essential to understandthe mechanisms involved.

Automated summary

Lipid bilayer membranes cannot adequately explain peptide-lipid interactions as a hydrophobic continuum solvent. Peptide diffusion should be understood in terms of free volume, not classical continuum mechanics. Peptide solubility or partitioning in membranes cannot be explained solely by hydrophobic mismatch, and the folding and translocation of peptides require the understanding that lipids adapt to their presence and may undergo lipid redistribution.