Solvation-Solvophobicity Interplay Drives Reentrant Swelling of Polymers in Poor Solvent Mixtures

While it is well established that a delicate balance between hydration and hydrophobic interactions governs the functional structures of proteins, a similar principle has received comparatively little attention in explaining the often-counterintuitive solution behavior of chemically simple synthetic polymers in mixed solvent environments. Using poly(methyl methacrylate) (PMMA) in water/tert-butanol mixtures as a model system, we demonstrate that the interplay between hydration and hydrophobicity can induce reentrant swelling of PMMA --- even though both water and tert-butanol are individually poor solvents for the polymer. Atomistic simulations reveal that changes in solution density upon mixing, previously proposed as a key driver of reentrant swelling, have negligible impact on PMMA conformation. Instead, the observed swelling correlates with a transition in local solvent composition -- from bulk-like to water-deficient -- regulated by a shifting balance between hydration and hydrophobic interactions associated with PMMA’s ester and alkyl groups, respectively. A theoretical model, informed by simulation insights, identifies two key effects arising from this interplay that drive the reentrant behavior: (1) the decoupled responses of hydration and hydrophobicity to solvent composition, and (2) composition-dependent effective repulsions between polymers, mediated by hydration-modulated hydrophobic interactions. These findings point to a general mechanism by which polymers bearing both solvation-prone and solvophobic moieties can exhibit cosolvency in mixed solvents, underscoring the critical role of solvation–solvophobicity interplay in governing polymer behavior in complex solution environments.