Flexible molecular docking: application of hybrid tabu-simplex optimisation

Abstract

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. A tabu-simplex optimisation is used: the best tabu solutions are refined using the Nelder-Mead Simplex optimisation. Most docking methods use scoring functions to approximate the binding affinity between two molecular partners. In our application, the intra-molecular and inter-molecular energies are calculated explicitly from a classical molecular mechanics model, which includes polarisation terms. The variables of our optimisation 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 genetic optimisation for ligand docking (GOLD) software 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.