Modeling kinase-substrate specificity: implication of the distance between substrate nucleophilic oxygen and attacked phosphorus of ATP analog on binding affinity

Molecular dynamics simulations were performed on modeled kinase-substrate complexes in an attempt to establish a relationship between structural features and binding ability of the complexes. We found that the monitored distance between substrate nucleophilic oxygen (OG) and attacked phosphorus (PG) of ATP analog correlated closely with the binding affinity. With reference to 3.3 Å, the van der Waals sum of oxygen and phosphorus, the calculated distances of good substrates were close to it whereas those of poor substrates were far apart from it. Therefore, it is reasonable to consider the OG-PG distance as a potential criterion to prefigure the kinase-substrate binding specificity and the simple computational techniques may work as an easy approach to distinguish good substrates from weak or poor substrates.