Calculations of the absolute binding free energies for Ralstonia solanacearum lectins bound with methyl-α-L-fucoside at molecular mechanical and quantum mechanical/molecular mechanical levels

A method that can reliably predict protein-ligand binding free energies is essential for rational drug design. Much effort has been devoted to this field, but it remains challenging especially for flexible ligands. In this work, both a molecular mechanical (MM) method and a hybrid quantum mechanical/molecular mechanical (QM/MM) method have been applied in the study of the binding affinities of methyl-a-L-fucoside to Ralstonia solanacearum lectins. The free energy at the MM level was calculated using the double-decoupling method (DDM) and the free energy change at each step was calculated via a series of intermediate states using the Bennett acceptance ratio (BAR). The binding free energy agrees well with the experimental measurement, no matter whether the general AMBER force field or GLYCAM06j was applied to the ligand. Nonetheless, slow convergence for some intermediate states has been observed, which requires substantially longer simulations than were used in many other studies. The QM/MM free energy was calculated by thermodynamic perturbation (TP) from the MM states. This strategy has been shown to yield minimal variance for the calculated free energy without direct sampling at the QM/MM level in a previous study. However, after this MM-to-QM/MM correction, the agreement with the experimental value decreased. This study serves as an implication of the demand for substantially longer simulations for the alchemical process than those that were used in many other studies and for further improvement of QM/MM methods, especially the description of interactions between the QM and MM regions.