Poly-L-leucine at interfaces.

Christophe Chipot and Andrew Pohorille

The undecamer of poly-L-leucine at the water-hexane interface is studied in molecular dynamics simulations. This represents a simple model relevant to folding and insertion of hydrophobic peptides into membranes. The peptide in a random coil conformation, initially placed on the aqueous side of the system, rapidly translocates towards the hexane phase and undergoes interfacial folding into an -helix in the subsequent 36 ns. Folding is non-sequential and highly dynamic. The helical stretch at the N-terminus of the undecamer becomes transiently broken and, then, reforms before the remainder of the peptide folds from the C-terminus. The formation of intramolecular hydrogen bonds during the folding of the peptide is preceeded by dehydration of the participating polar groups, as they become immersed in hexane. Folding proceeds through a short-lived intermediate, a 3-helix, which rapidly interconverts to an -helix. Both helices contribute to the equilibrium ensamble of folded structures. The helical peptide is largely buried in hexane but remains adsorbed at the interface. Its preferred orientation is parallel to the interface, although the perpendicular arrangement with the N-terminus immersed in hexane is only slightly less favorable. In contrast, the reversed orientation is highly unfavorable because it would require dehydration of carbonyl groups at the C-terminus which do not participate in intramolecular hydrogen bonding. For the same reason, the transfer of the undecamer from the interface to the bulk hexane is also unfavorable. The results suggest that hydrophobic peptides fold in the intrfacial region and, simulataneously, translocate to the non-polar side of the interface. Subsequently, they insert into the membrane by rotating from the parallel to the perpendicular orientation, most likely such that the N-terminus penetrates the bilayer. For snapshots of the folding structure click HERE.

Reference: ``Folding and translocation of the undecamer of poly-L-leucine across the water-hexane interface'', C. Chipot and A. Pohorille, J. Am. Chem.Soc., 120 11912-11924 (1998).

see also: ``Interactions of Small Molecules and Peptides in Membranes'', A. Pohorille, M. A. Wilson, C. Chipot, M. H. New and K. Schweighofer, in Computational Molecular Biology, (J. Leszczynski, Ed.), Elsevier, Amsterdam, 1999, pp 485-536.

``Early Events in the Folding of an Amphiphatic Peptide: A Multi-nanosecond Molecular Dynamics Study'', C. Chipot, B. Maigret and A. Pohorille, Proteins: Structure, Function, Genetics, 36, 383-399 (1999).