FMO
Here, we used the FMO method to compute the binding energy between the Trp-cage protein (PDB ID: 1L2Y; 20 residues with 304 atoms using the structure of the first isomer in the PDB file)74 and a water molecule, which was placed in the protein’s binding pocket. The protein–water complex is shown in Figure 10. The initial partial charges were obtained using the antechamber tool at the am1bcc level, and atom types in the general AMBER force field were assigned to the molecule,75,76 after which topology files were generated using LEaP in the antechamber tool.
We used the AMBER 201677 package, using 200 steps of minimization for the complex or separate ligand/protein, with the first 50 steps involving use of the steepest descent algorithm, followed by implementing the conjugate-gradient algorithm and then GridMol for fragment calculation. The FMO method and full-system computation were performed for comparison. Figure 11 shows the FMO process in GridMol, and a restricted Hartree–Fock method together with 6-31G(d) was used for single-point calculations. Full-system and FMO results were −0.446 and −0.453 kcal/mol, respectively, with a relative error of 1.6 %, which was within a reasonable range.