Self-Assembled Micellar Structures of Lipopeptides with Variable Number of Attached Lipid Chains Revealed by Atomistic Molecular Dynamics Simulations

We present atomistic molecular dynamics simulation study of the self-assembly behavior of toll-like agonist lipopeptides (PamnCSK4) in aqueous solutions. The variable number of hexadecyl lipid chains (n = 1, 2, 3) per molecule has been experimentally suggested to have remarkable influence on their self-assembled nanostructures. Starting from preassembled spherical or bilayer configurations, the aggregates of lipopeptides, PamCSK4 and Pam2CSK4, which contain peptide sequences CSK4 linked to either mono- or dilipid chains (Pam), evolve into spherical-like micelles within 30 ns, whereas the self-assembled structure of trilipidated lipopeptides, Pam3CSK4, relaxes much slower and reaches an equilibrium state of flattened wormlike micelle with a bilayer packing structure. The geometric shapes and sizes, namely the gyration radii of spherical micelles and thickness of the flattened wormlike micelle, are found to be in good agreement with experimental measurements, which effectively validates the simulation models and employed force fields. Detailed analyses of molecular packing reveal that these self-assembled nanostructures all consist of a hydrophobic core constructed of lipid chains, a transitional layer, and a hydrophilic interfacial layer composed of peptide sequences. The average area per peptide head at the interfaces is found to be nearly constant for all micellar structures studied. The packing parameter of the lipopeptide molecules thus increases with the increase of the number of linked lipid chains, giving rise to the distinct micellar shape transition from spherical-like to flattened wormlike geometry with bilayer stacking, which is qualitatively different from the shape transitions of surfactant micelles induced by variation of concentration or salt type. To facilitate the close-packing of the lipid chains in the hydrophobic core, the lipopeptide molecules typically take the bent conformation with average tilt angles between the peptide sequences and the lipid chains ranging from 110° to 140°. This consequently affects the orientation angles of the lipid chains with respect to the radial or normal direction of the spherical-like or flattened wormlike micelles. In addition, the secondary structures of the peptides may also be altered by the number of lipid chains to which they are linked and the resultant micellar structures. Our simulation results on the microscopic structural features of the lipopeptide nanostructures may provide potential insights into their bioactivities and contribute to the design of bioactive medicines or drug carriers. The force fields built for these lipopeptides and the geometric packing discussions could also be adopted for simulating and understanding the self-assembly behavior of other bioactive amiphiphiles with similar chemical compositions.