The unfolding transition of proteins in aqueous solution containing various salts or uncharged solutes is a classical subject of biophysics. In many cases, this transition is a well-defined two-stage equilibrium process which can be described by a free energy of transition ΔG u and a transition temperature T m. For a long time, it has been known that solutes can change T m profoundly. Here we present a phenomenological model that describes the change of T m with the solute concentration c s in terms of two effects: (i) the change of the number of correlated counterions Δn ci and (ii) the change of hydration expressed through the parameter Δw and its dependence on temperature expressed through the parameter dΔc p/dc s. Proteins always carry charges and Δn ci describes the uptake or release of counterions during the transition. Likewise, the parameter Δw measures the uptake or release of water during the transition. The transition takes place in a reservoir with a given salt concentration c s that defines also the activity of water. The parameter Δn ci is a measure for the gain or loss of free energy because of the release or uptake of ions and is related to purely entropic effects that scale with ln c s. Δw describes the effect on ΔG u through the loss or uptake of water molecules and contains enthalpic as well as entropic effects that scale with c s. It is related to the enthalpy of transition ΔH u through a Maxwell relation: the dependence of ΔH u on c s is proportional to the dependence of Δw on temperature. While ionic effects embodied in Δn ci are independent of the kind of salt, the hydration effects described through Δw are directly related to Hofmeister effects of the various salt ions. A comparison with literature data underscores the general validity of the model.
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