Quantum mechanical calculations for binding sites of metalloproteins

Abstract

Conventional docking methods which assume fixed charge model from force field parameters fail to predict right binding modes in a few groups of protein targets including metalloproteins. A new novel docking method with combined quantum mechanics/molecular mechanics (QM/MM) method has been applied to docking as a variable charge model and shown to exhibit improvement on the docking accuracy over fixed charge based methods. However, it has also been shown that there are a number of examples for which adoption of variable charge model fails to reproduce the native binding modes. The original implementation of QM/MM docking treated only ligands as quantum regions, which leaves metal ions present in binding sites with non-optimized charges. To address this problem, we extend the QM/MM docking method so that metal ions are included in quantum region, along with ligand atoms. This extension effectively rescales metal ion charge, but the results of docking experiment for binding mode prediction are unsatisfactory. Further analysis suggests that charge on metal ions transfers more greatly to surrounding protein atoms rather than ligand atoms, which explains the apparent over-correction of metal ion charge.