Conformational Dynamics of Phase-Separating Methacrylated Carbohydrates

Polysaccharide-based materials, particularly dextran (Dex) derivatives, have emerged as versatile platforms for biomedical and materials science applications primarily due to their tunable chemical functionality and intrinsic biocompatibility. Native Dex is a highly hydrophilic molecule and does not inherently exhibit phase separation; however, recent experimental studies have shown that systematically introducing hydrophobic methacrylate groups on the Dex backbone induces phase separation, presumably due to hydrophilic/hydrophobic partitioning of interactions. In this work, we employed all-atom molecular dynamics (MD) simulations to probe the effect of site-specific methacrylation on the conformational dynamics of the individual chains as well as on the intermolecular interactions and aggregation. We generated atomistic models of all possible mono-, di-, and trisubstituted repeating units and further constructed Dex chains of varying lengths and degrees of methacrylation. Our simulations revealed that methacrylation consistently promotes chain compaction, with increasing degrees of methacrylation yielding progressively more globular conformations. This structural transition was accompanied by reduced intramolecular hydrogen bonding, decreased polysaccharide-water interactions, and enhanced interactions between methacrylate groups, indicating that compaction is primarily induced by hydrophobic interactions rather than hydrogen bonding. In multichain systems, variants exhibiting the greatest chain compaction also displayed the strongest aggregation propensity, resulting in the formation of stable hydrated polymer-rich assemblies. Our results revealed the molecular details of chain compaction and phase separation induced by conjugating methacrylate groups to a hydrophilic carbohydrate.