Elucidating β-Sheet Ordering in Lipopeptides Bearing Lysine-Rich Tripeptide Sequences: Fibrils versus Nanotapes.

The self-assembly in aqueous solution and conformation of lipopeptides C16-WKK, C16-KWK, C16-YKK and C16-KYK is compared and examined. Remarkable differences are observed among the systems despite the small sequence changes comparing C16-XKK with the C16-KXK homologue (X = W or Y), depending on pH. These are rationalized using a molecular theory for amphiphile self-assembly (MOLT) to predict the morphology along with atomistic molecular dynamics simulations to probe local conformation and packing, along with new experimental data from small-angle X-ray scattering (SAXS) and FTIR spectroscopy. MOLT correctly describes the high-pH morphology behavior, i.e., fibrils for C16-XKK, and lamellar nanotapes for C16-KXK, although it predicts micelles for all systems at low pH, whereas experiments indicate that this only occurs for the C16-XKK lipopeptides, not the C16-KXK, which form lamellar nanotapes stable over an extended range of pH 2-12. Atomistic MD reveals β-sheet conformation is more favored for the C16-XKK lipopeptides which also have enhanced aggregation propensity compared to C16-KXK analogues. The extent of π-stacking was higher for the latter lamellar nanotape structures. The extent of hydrogen bonding is higher for the tyrosine-containing molecules than the tryptophan-based ones. The combination of a molecular theory and atomistic MD provides a comprehensive insight into the remarkable sequence- and pH-dependent molecular ordering within these model lipopeptides which will enable the rational design of future peptide amphiphiles with targeted nanostructures for desired applications.