Studies carried using engineered proteins have demonstrated that protein adsorption to functional surfaces involves multiple interactions between specific groups on the protein and complementary binding sites distributed on the surface. A consequence of multipoint interactions is that protein binding affinity should depend strongly on the distribution of surface binding sites. In this investigation we present a thermodynamic framework for multipoint protein binding to a random arrangement of surface binding sites that also includes lateral interactions among adsorbed protein molecules. This framework results in reversible adsorption behavior analogous to that predicted by the Temkin model and chromatographic behavior analogous to that predicted by the "stoichiometric displacement" model (SDM). Using this framework we can now interpret the semiempirical parameters obtained using these models for protein binding in chromatographic systems in terms of thermodynamic parameters for protein-surface interactions. We show a correlation between Temkin model parameters for a series of cytochrome c variants in immobilized metal affinity chromatography (IMAC) that is consistent with protein adsorption to a nonuniform arrangement of surface binding sites. Lateral interactions among adsorbed protein molecules are shown to be insignificant for this system.