Flexible molecular docking: application of hybrid tabu-simplex optimisation

In this paper, we present a molecular docking method to predict the optimal binding pose of a flexible ligand in a flexible protein-binding pocket. For this purpose, a Tabu global search optimization algorithm is used, and the best Tabu solutions are then refined using the Nelder-Mead Simplex local search optimization algorithm. Most docking methods use scoring functions to approximate the binding affinity between the two molecular partners. In our application, the intra-molecular and intermolecular energies are calculated explicitly from a classical molecular mechanics model, which includes polarization terms. The variables of our optimization problem are the ligand positions (Euler angles + translation vector), the ligand and the protein side chains dihedral angles instead of the Cartesian coordinates in order to reduce the problem dimensionality. While the GOLD software (GOLD for Genetic Optimization for Ligand Docking) is usually considered as a standard in molecular docking, our docking approach is illustrated on four protein/ligand complexes for which GOLD failed, suggesting that the proposed method is promising.