FOLDING AND TRANSLOCATION OF THE UNDECAMER OF POLY-L-LEUCINE ACROSS THE WATER-HEXANE INTERFACE - A MOLECULAR-DYNAMICS STUDY

The undecamer of poly-L-leucine at the water-hexane interface is studi ed by molecular dynamics simulations. This represents a simple model r elevant to folding and insertion of hydrophobic peptides into membrane s. The peptide, initially placed in a random coil conformation on the aqueous side of the system, rapidly translocates toward the hexane pha se and undergoes interfacial folding into an alpha-helix in the subseq uent 36 ns. Folding is nonsequential and highly dynamic. The initially formed helical segment at the N-terminus of the undecamer becomes tra nsiently broken and, subsequently, reforms before the remainder of the peptide folds from the C-terminus. The formation of intramolecular hy drogen bonds during the folding of the peptide is preceded by a dehydr ation of the participating polar groups, as they become immersed in he xane. Folding proceeds through a short-lived intermediate, a 3(10)-hel ix, which rapidly interconverts to an alpha-helix. Both helices contri bute to the equilibrium ensemble of folded structures. The helical pep tide is largely buried in hexane, yet remains adsorbed at the interfac e. Its preferred orientation is parallel to the interface, although th e 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 C-terminu s carbonyl groups that do not participate in intramolecular hydrogen b onding. For the same reason, the transfer of the undecamer from the in terface to the bulk hexane is also unfavorable. The results suggest th at hydrophobic peptides fold in the interfacial region and, simultaneo usly, translocate into the nonpolar side of the interface. It is furth er implied that peptide insertion into the membrane is accomplished by rotating from the parallel to the perpendicular orientation, most lik ely in such a way that the N-terminus penetrates the bilayer.