The Planck-Benzinger thermal work function Delta W(T) represents the strictly thermal components of any intra- or intermolecular bonding term in a system, that is, energy other than the inherent difference of the 0 K portion of the interaction energy. The latter, the temperature-invariant enthalpy, is the only energy term at absolute zero Kelvin. The magnitude of Delta H(T-0) or Delta H degrees(T-0), the temperature-invariant enthalpy, is determined by the type of macromolecular interaction taking place under experimental conditions, and thus, this thermodynamic function should be particularly applicable to studies on the ribonuclease S-protein interaction with S-peptides with various substitutions at methionine-13. Values for Delta H(T-0) for the S-protein-S-peptides interaction with such substitution at Met-13 were determined to be 25.67 +/- 0.63 (Met-13 --> Ala), 85.69 +/- 0.35 (Met-13 --> Phe), and 22.32 +/- 0.19 kcal mol(-1) (Met-13 --> alpha-amino-N-butyric acid). A possible model for the fragment complementation reaction of S-peptide with S-protein if phenylalanine were to be substituted for Met-13 is proposed. The model incorporates feasible strong, site-specific Phe-Phe interaction, giving rise to the large temperature-invariant enthalpy. This thermodynamic approach should be an essential component of all future studies involving the site-directed, mutagenic approach to the examination of structure-function problems in proteins.