Application of QM/MM Calculations with Novel
Polarized Embedding to Detail Investigation of the Flavoprotein
WrbA
David Øeha, Vasilina Zayats,
Rüdiger Ettrich
The mechanisms of NADH:quinine oxidation reduction reaction in flavoprotein WrbA was studied by improved molecular docking based on the novel implementation of QM/MM method with polarized embedding. The molecular docking estimates the positions and relative binding energies of the substrates of the flavoprotein WrbA and thus can lead to better understanding of the mechanisms of NADH:quinine oxidation reduction reaction.
Standard molecular docking estimates the positions and binding energies of the flexible ligand to the rigid protein. The binding energies are calculated by nonpolarized molecular mechanical (MM) forcefield. This approach is appropriate for the study of the wide variety of the ligands, however it can fail in the case of the electrically charged ligands, like NADH and quinine in flavoprotein, where the charge is transferred from ligand to the protein cofactor and the polarization effects become very significant and cannot be neglected.
The polarization in molecular docking was introduced via atomic charges derived from QM/MM calculations with polarized embedding. The ligand (QM part) charges were derived from quantum mechanical (QM) electronic wave function and polarized charges of the rigid protein (MM part) were derived by the novel method of induced charges1. This approach is based on the method of induced dipoles, where the induced dipole on particular atom (calculated from atomic polarizability) is approximated by the set of induced charges on the neighboring atoms. This brings a considerable simplification and allows the use of standard programs for molecular docking, as they already evaluate electrostatic interactions using atomic charges.
The authors gratefully acknowledge financial support from grant Kontakt ME09016.
[1] Ferenczy, G.G.; Reynolds, C.A. J. Phys. Chem. A 2001, 105, 11470–11479.