The Relationship Between Cooperativity of a Ligand-Protein Complex and Its Ligand Binding Site Location

Cooperativity, the ability of the binding of one ligand to change the binding affinity of subsequent ligands, is an important biological characteristic of proteins, the mechanism of which is still unknown. To gain insight into the underlying mechanism of cooperativity, it is desirable to connect the thermodynamic explanations of cooperativity, i.e., the MWC and KNF models, to a structural basis. More precisely, this thesis explores the relationship between the location of the ligand binding site and cooperativity of the ligand-protein complex. I propose that interfacial ligand binding sites imply negative cooperativity and internal binding sites imply positive cooperativity. I analyzed 16 ligand-multimer complexes with identical subunits by classifying (1) the ligand binding site locations using ligand-protein crystal structures and (2) the cooperativities of the ligand-protein complexes by comparing the best-fit non-cooperative and cooperative curves modeled using the Adair equation. Out of the 16 ligand-protein systems analyzed, 10 systems were consistent with the hypothesis, 2 – inconsistent, and 4 – inconclusive. In conclusion, I found that the location of the ligand binding site seems to influence the type of cooperativity (positive or negative) with a significance level of α < 0.05