Origin of heat capacity increment in DNA folding: The hydration effect

Understanding DNA folding thermodynamics is crucial for prediction of DNA thermal stability. It is now well established that DNA folding is accompanied by a decrease of the heat capacity ∆c_{p, F}, however its molecular origin is not understood. In analogy to protein folding it has been assumed that this is due to dehydration of DNA constituents, however no evidence exists to support this conclusion.

Here we analyze partial molar heat capacity of nucleic bases and nucleosides in aqueous solutions obtained from calorimetric experiments and calculate the hydration heat capacity contribution ∆c_p^hyd.

We present hydration heat capacity contributions of DNA constituents and show that they correlate with the solvent accessible surface area. The average contribution for nucleic base dehydration is +0.56 J mol^-1 K^-1 Å^-2 and can be used to estimate the ∆c_{p, F} contribution for DNA folding.

We show that dehydration is one of the major sources contributing to the observed ∆c_{p, F} increment in DNA folding. Other possible sources contributing to the overall ∆c_{p, F} should be significant but appear to compensate each other to high degree. The calculated ∆c_p^hyd for duplexes and noncanonical DNA structures agree excellently with the overall experimental ∆c_{p, F} values. By contrast, empirical parametrizations developed for proteins result in poor ∆c_p^hyd predictions and should not be applied to DNA folding.

Heat capacity is one of the main thermodynamic quantities that strongly affects thermal stability of macromolecules. At the molecular level the heat capacity in DNA folding stems from removal of water from nucleobases.