Molecular dynamics simulations followed by quantum mechanical calculation and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis have been carried out to study binding of proline- and pyrazinone-based macrocyclic inhibitors (L86 and T76) to human α-thrombin. Detailed binding interaction energies between these inhibitors and individual protein fragments are calculated using DFT method based on a new quantum mechanical approach for computing protein-ligand interaction energy. The analysis of detailed interaction energies provides insight on the protein-ligand binding mechanism. Study shows that T76 and L86 bind to thrombin in a very similar "inhibition mode" except that T76 has relatively weaker binding interaction with Glu217. The analysis from quantum calculation of binding interaction is consistent with the MM-PBSA calculation of binding free energy, and the calculated free energies for L86/T76-thrombin binding agree well with the experimental data.
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