Entropy-Driven Stabilization of Highly Charged Peptoid Nanosheets

Free-standing two-dimensional (2D) peptoid nanosheets are promising for many aqueous applications, yet how the ionic environment governs their structure and thermal stability remains poorly understood. Here we design an ultrathin (∼2 nm) crystalline peptoid nanosheet with an extremely small ionizable (ethylammonium) polar domain as a structurally well-defined, highly charged model system, whose molecular packing is directly resolved by cryogenic electron microscopy. Solution-state differential scanning calorimetry reveals that salt-induced stabilization is dominated by entropy rather than enthalpy. Our Molecular Dynamics (MD) simulations attribute this to the release of surface-condensed counterions upon melting, which is set by both the surface’s counterion-condensing capacity and the bulk ion concentration, with our computed release entropies tracking the measured melting entropies. With sodium halide salts, the melting temperatures follow a Hofmeister-like ordering (F– > Cl– > Br–), reflecting F– ’s higher propensity for contact ion pairing with the N-terminal ammonium groups, as demonstrated by our MD simulations. Bulky organic cations such as tetrabutylammonium add enthalpic stabilization, which we ascribed to the direct dispersion contacts with hydrophobic surface groups between their alkyl chains of tetrabutylammonium and hydrophobic surface-exposed side chains, whereas Na+ does not. By resolving how ion identity partitions stabilization between entropic and enthalpic interfacial pathways, this work establishes electrolyte composition as a key design parameter for tuning free-standing, highly charged 2D soft materials.