Quantum-Chemical Quasi-Docking for Molecular Dynamics Calculations

Abstract

The quantum quasi-docking procedure is used to compare the docking accuracies of two quantum-chemical semiempirical methods, namely, PM6-D3H4X and PM7. Quantum quasi-docking is an approximation to quantum docking. In quantum docking, it is necessary to search directly for the global minimum of the energy of the protein-ligand complex calculated by the quantum-chemical method. In quantum quasi-docking, firstly, we look for a wide spectrum of low-energy minima, calculated using the MMFF94 force field, and secondly, we recalculate the energies of all these minima using the quantum-chemical method, and among these recalculated energies we determine the lowest energy and the corresponding ligand position. Both PM6-D3H4X and PM7 are novel methods that describe well-dispersion interactions, hydrogen and halogen bonds. The PM6-D3H4X and PM7 methods are used with the COSMO implicit solvent model as it is implemented in the MOPAC program. The comparison is made for 25 high quality protein-ligand complexes. Firstly, the docking positioning accuracies have been compared, and we demonstrated that PM7+COSMO provides better positioning accuracy than PM6-D3H4X. Secondly, we found that PM7+COSMO demonstrates a much higher correlation between the calculated and measured protein–ligand binding enthalpies than PM6-D3H4X. For future quantum docking PM7+COSMO is preferable, but the COSMO model must be improved.

Keywords

• docking
• quantum chemistry
• supercomputing
• drug design
• inhibitor
• target protein