The thermodynamic parameters for six p53 carboxy-terminus peptide fragments as determined by analytical ultracentrifugal analysis were compared over the experimental temperature range of 275-310 K to evaluate the Gibbs free energy change as a function of temperature, ΔGo(T), from 0 to 400 K using our general linear third-order fitting function, ΔGo(T) = α + βT2 + γT3. Data obtained at the typical experimental temperature range are not sufficient to accurately describe the variations observed in the oligomerization of these p53 fragments. It is necessary to determine a number of thermodynamic parameters, all of which can be precisely assessed using this general third-order linear fitting function. These are the heat of reaction, innate temperature-invariant enthalpy, compensatory temperatures and the thermodynamic molecular switch occurring at the thermal set point. The temperature-invariant enthalpy for each of the six p53 peptide fragments was found to be: Lys319-Ala347, 10.92 kcal mol−1; Lys319-Lys351, 24.75; Lys319-Gly360, 54.86; Lys319-Asp393, 203.20; Ser303-Asp393, 140.43; and Ser303-Gly360, 49.69 kcal mol−1. While the role of the C-terminus in sequence-specific DNA binding has been debated, these results suggest that the C-terminal end has a significant influence on the degree of oligomerization in p53. When p53 is considered in vivo, it would seem that the C-terminus has an additional role, that of protecting the tetramerization domain. These thermodynamic values can be used to distinguish the characteristic structure and stability not only of p53 carboxy-terminal fragments or other p53 mutants, but also in the analysis of site-direct mutagenesis or other fragmentation, deletion mutation, and truncation reactions. In fact the parameters determined with this universal linear third-order fitting function are essential for the thermodynamic characterization of any interacting biological system. No other experimental method offers a similar degree of accuracy.