Mass action models versus the Hill model: An analysis of tetrameric human thymidine kinase 1 positive cooperativity

BACKGROUND: The Hill coefficient characterizes the extent to which an enzyme exhibits positive or negative cooperativity, but it provides no information regarding the mechanism of cooperativity. In contrast, models based on the equilibrium concept of mass action can suggest mechanisms of cooperativity, but there are often many such models and often many with too many parameters. RESULTS: Mass action models of tetrameric human thymidine kinase 1 (TK1) activity data were formed as pairs of plausible hypotheses that per site activities and binary dissociation constants are equal within contiguous stretches of the number of substrates bound. Of these, six 3-parameter models were fitted to 5 different datasets. Akaike's Information Criterion was then used to form model probability weighted averages. The literature average of the 5 model averages was K = (0.85, 0.69, 0.65, 0.51) μM and k = (3.3, 3.9, 4.1, 4.1) sec(-1 )where K and k are per-site binary dissociation constants and activities indexed by the number of substrates bound to the tetrameric enzyme. CONCLUSION: The TK1 model presented supports both K and k positive cooperativity. Three-parameter mass action models can and should replace the 3-parameter Hill model. REVIEWERS: This article was reviewed by Philip Hahnfeldt, Fangping Mu (nominated by William Hlavacek) and Rainer Sachs.