Thermodynamic anatomy of micelle-small molecule coacervation

Although polymer-based coacervates have long been a research focus, their large molecular weight and sluggish response to external stimuli motivate the study of simpler micelle-small molecule systems. Here, we use coarse-grained simulations with umbrella sampling-explicitly incorporating solvent water-to investigate the coacervation of a charged amphiphile and a multivalent countercharged compound, elucidating both the kinetic pathways and thermodynamic driving forces. Our results show that coacervation proceeds through initial pairing of multivalent ions with self-assembled amphiphile micelles, followed by Brownian motion-driven coalescence-rather than by Ostwald ripening, the dominant growth mechanism in traditional micellization systems with monovalent counterions. Both stages are primarily governed by entropy rather than enthalpy. This entropy gain arises from the release of counterions and their hydration shells, as well as from the dehydration of the coacervate complex, marked by the contact of the first water shell. The consequent reduction in ion-solvent interactions incurs unfavorable ion-dipole contributions to the overall enthalpy. In highlighting water's critical role, our findings shed light on how molecular details govern phase behavior and physical properties in micelle-small molecule coacervate systems.