(181x) Free Energy Landscape for Lower Critical Solution Temperature Transition of Thermoresponsive Poly(N-isopropylacrylamide)

Thermo-responsive polymers exhibit hydrophobic−hydrophilic phase transition at their lower critical solution temperatures (LCST). For poly(N-isopropylacrylamide) (PNIPAM), the LCST phase transition is due mainly to the presence of a hydrophilic amide group on the side chain and a hydrophobic isopropyl group in each NIPAM unit as well as a hydrophobic C-C backbone. However, the driving force for the LCST transition, particularly at the molecular level remains controversial and unresolved. Here classical molecular dynamics simulations coupled with metadynamics technique was used to investigate the free energies associated with the folding and unfolding processes (i.e. hydrophobic-hydrophilic transition) of PNIPAM in water at the transition temperature of 305 K. In addition, the role of intermolecular and intramolecular hydrogen bonding interactions on the LCST transitions was also elucidated. Our results indicate that LCST is mainly entropically driven and that unfolding process has a higher barrier and is energetically less favored compared to the folding process at the transition temperature.