Mechanism of globule-to-coil transition of poly(N-isopropylacrylamide) in water: Relevance to cold denaturation of a protein

In water, poly(N-isopropylacrylamide) (PNIPAM) is in a soluble coil state below the lower critical soluble temperature (LCST) but in an insoluble globule state above LCST. Namely, as the temperature decreases, PNIPAM exhibits a globule-to-coil transition at LCST~305 K. We generate structural ensembles of coil and globule states by all-atom molecular dynamics simulations conducted at 273 and 323 K, respectively. We then calculate a variety of energetic and entropic components of thermodynamic quantities of the two states at the two temperatures using our recently developed, accurate statistical-mechanical method for solute hydration where molecular models are employed for water and the PNIPAM structure is taken into account at the atomic level. We identify the physical factors driving or opposing the transition and evaluate their relative magnitudes and temperature dependences. The presence of PNIPAM generates an excluded volume (EV) which is inaccessible to the centers of water molecules in the entire system. The presence of a water molecule also generates an EV for the other water molecules with the result that all of the water molecules are entropically correlated, causing water crowding. The globule state, where the EV is smaller and water crowding is less significant, is more favored in terms of the translational, configurational entropy of water. This effect always opposes the globule-to-coil transition. At low temperatures, however, this effect becomes significantly weaker, yielding to the factors driving it. The mechanism of the transition is physically the same as that of cold denaturation of a protein.