Unraveling the Role of Charge Patterning in the Micellar Structure of Sequence-Defined Amphiphilic Peptoid Oligomers by Molecular Dynamics Simulations

[Image: see text] Electrostatic interactions play a significant role in regulating biological systems and have received increasing attention due to their usefulness in designing advanced stimulus-responsive materials. Polypeptoids are highly tunable N-substituted peptidomimetic polymers that lack backbone hydrogen bonding and chirality. Therefore, polypeptoids are suitable systems to study the effect of noncovalent interactions of substituents without complications of backbone intramolecular and intermolecular hydrogen bonding. In this study, all-atom molecular dynamics (MD) simulations were performed on micelles formed by a series of sequence-defined ionic polypeptoid block copolymers consisting of a hydrophobic segment and a hydrophilic segment in an aqueous solution. By combining the results from MD simulations and experimental small-angle neutron scattering data, further insights were gained into the internal structure of the formed polypeptoid micelles, which is not always directly accessible from experiments. In addition, information was gained into the physics of the noncovalent interactions responsible for the self-assembly of weakly charged polypeptoids in an aqueous solution. While the aggregation number is governed by electrostatic repulsion of the negatively charged carboxylate (COO(–)) substituents on the polypeptoid chain within the micelle, MD simulations indicate that the position of the charge on singly charged chains mediates the shape of the micelle through the charge–dipole interactions between the COO(–) substituent and the surrounding water. Therefore, the polypeptoid micelles formed from the single-charged series offer the possibility for tailorable micelle shapes. In contrast, the polypeptoid micelles formed from the triple-charged series are characterized by more pronounced electrostatic repulsion that competes with more significant charge–sodium interactions, making it difficult to predict the shape of the micelles. This work has helped further develop design principles for the shape and structure of self-assembled micelles by controlling the position of charged moieties on the backbone of polypeptoid block copolymers.