Quantum-Chemical Quasi-Docking for Molecular Dynamics Calculations

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Accurate prediction of protein-ligand interactions is crucial for drug discovery.
• Quantum chemical methods offer high accuracy but are computationally intensive.
• Semiempirical quantum chemical methods provide a balance between accuracy and efficiency.

Purpose of the Study:

• To compare the docking accuracies of PM6-D3H4X and PM7 quantum chemical methods using the quantum quasi-docking approach.
• To evaluate the performance of these methods in describing protein-ligand interactions, including dispersion forces, hydrogen bonds, and halogen bonds.
• To assess the correlation between calculated and experimental binding enthalpies for protein-ligand complexes.

Main Methods:

• Utilized the quantum quasi-docking procedure, an approximation to quantum docking, for comparing docking accuracies.
• Employed MMFF94 force field to identify low-energy minima, followed by quantum chemical re-evaluation using PM6-D3H4X and PM7 with the COSMO implicit solvent model.
• Compared results for 25 high-quality protein-ligand complexes.

Main Results:

• PM7+COSMO demonstrated superior positioning accuracy compared to PM6-D3H4X.
• PM7+COSMO exhibited a significantly higher correlation between calculated and measured protein-ligand binding enthalpies.
• Both methods effectively describe dispersion interactions, hydrogen bonds, and halogen bonds.

Conclusions:

• The PM7+COSMO method is preferable for future quantum docking applications due to its enhanced accuracy and correlation with experimental binding data.
• Further improvements to the COSMO implicit solvent model are recommended for even greater accuracy in quantum docking simulations.
• The quantum quasi-docking approach provides a viable strategy for evaluating quantum chemical methods in molecular docking.