| Abstract
| - Pairwise decomposition of the interaction energy between molecules is shown to be a powerfultool that can increase our understanding of macromolecular recognition processes. Herein we calculatethe pairwise decomposition of the interaction energy between the protein human carbonic anhydrase II(HCAII) and the fluorine-substituted ligand N-(4-sulfamylbenzoyl)benzylamine (SBB) using semiempiricalquantum mechanics based methods. We dissect the interaction between the ligand and the protein bydividing the ligand and the protein into subsystems to understand the structure−activity relationships as aresult of fluorine substitution. In particular, the off-diagonal elements of the Fock matrix that is composedof the interaction between the ionic core and the valence electrons and the exchange energy between thesubsystems or atoms of interest is examined in detail. Our analysis reveals that the fluorine-substitutedbenzylamine group of SBB does not directly affect the binding energy. Rather, we find that the strength ofthe interaction between Thr199 of HCAII and the sulfamylbenzoyl group of SBB affects the binding affinitybetween the protein and the ligand. These observations underline the importance of the sulfonamide groupin binding affinity as shown by previous experiments (Maren, T. H.; Wiley: C. E. J.Med.Chem.1968, 11,228−232). Moreover, our calculations qualitatively agree with the structural aspects of these protein−ligand complexes as determined by X-ray crystallography.
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