Why small proteins tend to have high denaturation temperatures

Data indicate that small globular proteins (consisting of less than about 70 residues) tend to have high denaturation temperatures. This finding is analysed by comparing experimental denaturation enthalpy and entropy changes of a selected set of small proteins with values calculated on the basis of average and common properties of globular proteins. The conclusion is that the denaturation entropy change is smaller than expected, leading to an increase in denaturation temperature. The proposed molecular rationalization considers the existence of long-wavelength, low-frequency vibrational modes in the native state of small proteins due to their large surface-to-interior ratio. The effect of decreasing the conformational entropy gain associated with denaturation on thermal stability is directly verified by means of an already devised theoretical model [G. Graziano, Phys. Chem. Chem. Phys. 2010, 12, 14245-14252; 2014, 16, 21755-21767].