Semiempirical Quantum Mechanical Method PM6-DH2X Describes the Geometry and Energetics of CK2-Inhibitor Complexes Involving Halogen Bonds Well, While the Empirical Potential Fails

• Published in: The journal of physical chemistry. B Vol. 115; no. 26; pp. 8581 - 8589
• Main Authors: Dobeš, Petr, Řezáč, Jan, Fanfrlík, Jindřich, Otyepka, Michal, Hobza, Pavel
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07-07-2011
• Subjects: B: Biophysical Chemistry; Bonding; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - chemistry; Constants; Empirical analysis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Free energy; Halogenation; Halogens; Halogens - chemistry; Kinases; Models, Molecular; Molecular Structure; Protein Binding; Protein Conformation; Proteins; Quantum mechanics; Quantum Theory; Thermodynamics
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp202149z

In the present study, we have investigated complexes of CK2 protein kinase with halogenated inhibitors by means of the advanced semiempirical quantum mechanical (SQM) PM6 method (called PM6-DH2X), which describes various types of noncovalent interactions including halogen bonding well. The PM6-DH2X method provides reliable geometries of those CK2 protein kinase-inhibitor complexes involving halogen bonds that agree well with the X-ray crystal structures. When the Amber empirical potential is applied, this agreement becomes considerably worse. Similarly, the binding free energies determined by the PM6-DH2X SQM method are much closer to the experimental inhibition constants than those based on the Amber empirical potential.