Hydration‐Interaction Balance Controls Morphological Landscapes in Peptide‐Polymer Amphiphiles

ABSTRACT

Peptide‐polymer amphiphiles (PPAs) form diverse nanostructures with tunable properties, yet predicting and tuning these morphologies remains challenging due to complex molecular interactions. We systematically investigated the self‐assembly of PPAs with a random coil peptide (XTEN2) base and varying side chains of an oligo (alkyl acrylate) tail (ethyl, n ‐butyl, tert ‐butyl, hexyl, and cyclohexyl) using large‐scale all‐atom molecular dynamics (AMD) simulations validated by experimental observations. Our results revealed that the formation of various micellar morphologies, such as worm‐like, perforated, spherical, and multi‐core assemblies, is governed by the balance between tail‐to‐tail and tail‐to‐water interaction energies, in addition to core hydration levels. Spherical and multi‐core morphologies form when tail‐to‐tail interactions dominate, whereas worm‐like and perforated structures form as tail‐to‐water interactions increase. Additionally, peptide secondary structure dictated by sequence plays an important role in driving assembly, with β‐sheet‐rich conformations promoting more compact cores. These findings elucidate how subtle tail architecture variations direct PPA self‐assembly, providing molecular‐level insights that align with experimental particle sizes. This work advances the rational design of PPA‐based nanomaterials by linking molecular interactions to morphology control.