Folding Peptides Into Lipid Bilayer Membranes

Abstract

The folding and integration of peptides into lipid bilayers remains one of the most intriguing processes in biophysics, as it cannot be directly observed at sufficient temporal and spatial resolutions. From a physical chemistry perspective transfer of solvated peptides into a hydrocarbon phase should follow a two-stage pathway, where helical segments fold at the phase boundary before inserting, due to the large energetic penalty associated with de-solvating exposed peptide bonds.The adsorption, folding and membrane insertion of a model peptide (WALP) was studied via microsecond-timescale molecular simulations at atomic resolution. Both an implicit model and an explicit lipid bilayer setup were used. The implicit simulations generally follow the theoretically predicted two-stage pathway. The vastly increased sampling yields fully converged thermodynamic properties such as the free-energy of folding and membrane insertion. In contrast, the explicit bilayer simulations show that after spontaneous adsorption the peptide immediately crosses the polar interface to locate at the hydrophobic membrane core. Remarkably, there is no interfacial state and the dominant configurations are deeply inserted unfolded and beta-hairpin conformers. The native trans-membrane helix formed for several hundred nanoseconds is not stable. At present the reasons for this unexpected behavior remain unclear.View Large Image | View Hi-Res Image | Download PowerPoint Slide