Molecular recognition of ligands by proteins is a subject of great importance for understanding enzymatic mechanisms and for drug design. The molecular determinants for the high affinity binding of biotin to streptavidin were analyzed by computer simulations based on first principles. Because of algorithmic and computational technology advances, we were able to carry out two challenging high level quantum mechanics simulations of the streptavidin-biotin complex: (1) geometry optimization of the streptavidin-biotin complex using a hybrid quantum mechanics/molecular mechanics (QM/MM) method; (2) ab initio electronic structure calculations of intermolecular interaction energies by means of the supermolecular approach at the MP2/6-311+G* level with solvation free energy correction using the SM5.42R model. The optimized complex enabled a topological analysis of the electron density in the framework of the Atoms-in-Molecules (AIM) Theory, which provided, for the first time, direct evidence for the hypothesized resonance enhanced polarization of hydrogen bonding in the streptavidin-biotin complex. Our simulations attribute the strong binding affinity between biotin and streptavidin to a dominant hydrogen bonding network between the ureido group and its surrounding residues. Knowledge gained here about the interactions between ligands and their target proteins will be valuable in understanding the fundamental process of molecular recognition and will aid in the design of novel ligands and potent drugs.
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