Scoring functions typically make the assumption that the non-covalent interactions contribute in an additive way for the ligand-protein binding affinity. In our previous study we revealed strong positive functional group cooperativity between a hydrogen bonding group and aliphatic side chains for a series of thrombin inhibitors.  The positive cooperativity was due to the hydrogen bonding group restricting the motion of the side chains inside their hydrophobic pocket, and vice versa. In the current study we evaluated the affect of the ligand rigidity imparted by a proline ring on the magnitude of this cooperativity.  The results demonstrated a large reduction in the magnitude of positive cooperativity when the rigidity of the proline ring was removed with open chain analogs.  Consequently, ligand flexibility needs to be accounted for when predicting the magnitude of functional group cooperativity.

Effect of ligand rigidity on binding cooperativity between H-bond and hydrophobic side chains: A case study with thrombin inhibitors

246th National Meeting (2013)

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