Influence of the method of hydrogen atoms incorporation into the target protein on the protein-ligand binding energy

Preparation of the target-protein, particularly the protein protonation method can affect considerably the spatial arrangement of the attached hydrogen atoms and the charge state of individual molecular groups in amino acid residues. This means that the calculated protein-ligand binding energies can vary significantly depending on the method of the protein preparation, and it also can lead to the different docked positions of the ligand in the case of docking (positioning of the ligand in the protein active site). This work investigates the effect of the hydrogen atoms arrangement method in the target-protein on the protein-ligand binding energy. All hydrogen atoms of target-protein are fixed or movable. The comparison of the protein-ligand binding energies obtained for the test set of target-proteins prepared using six different programs is performed and it is shown that the protein-ligand binding energy depends significantly on the method of hydrogen atoms incorporation, and differences can reach $100$ kcal/mol. It is also shown that taking into account solvent in the frame of one of the two continuum implicit models smooths out these differences, but they are still about $10$–$20$ kcal/mol. Moreover, we carried out the docking of the crystallized (native) ligands from the protein-ligand complexes using the SOL program and showed that the different methods of the hydrogen atoms addition to the protein can give significantly different results both for the positioning of the native ligand and for its protein-ligand binding energy.