MFCC
We used different QM methods to calculate binding free energy for two complex systems.78 As shown in Figure 14, the complex systems comprised a protein built according to a crystal structure (PDB ID: 3FLY) and two different ligands (PDB IDs: 3FMH and 3FLZ). First, the initial partial charges are obtained using the antechamber tool at the am1bcc level, and the atom types in GAFF are assigned to the two molecules. LEaP is then used for rapid generation of topology files for use with the AMBER simulation. The structures are minimized initially, using steepest descent for the first 50 cycles and then conjugate gradient for 150 cycles with an implicit solvent model. The systems are then gradually heated 100 K every 5 ps from 50 K to 300 K, after which the systems are equilibrated for 10 ps. We then collected an MD simulation for 1 ns with a 1-fs time step, and GridMol was used to load the relaxed system and perform autofragmentation. We used different QM methods, together with the 6-31G(d,p) basis set in the Gaussian 16 package, to calculate the energy of each fragment, cap, and ligand. Additionally, we used the AMBER ff9SB force field to calculate the energy of the protein–ligand complex and the protein and ligand separately.
we conducted a comparative study to investigate the performance of widely used quantum mechanical methods in the treatment of the protein and ligands, including available functionals representing hybrid GGA (B3LYP and PBE0), meta-GGA (TPSS), hybrid meta-GGA (M06 and M06-2X), range-separated hybrid GGA (CAM-B3LYP and ωB97XD), global-hybrid meta-NGA (MN15) classes, and the MP2 method.79-85
The interaction energies calculated by the AMBER ff99SB force field for 3FMH and 3FLZ were −122.99 kcal/mol and −38.99 kcal/mol, respectively. Table 1 shows the MFCC calculation results, which were almost the same order of magnitude as the AMBER force field. This suggested that the fragmentation steps were correct for the two complexes. We used the calculated results for the MP2 method as a reference of reliability. The complex, with 5640 atoms, was fragmented into 1387 fragments, with the number of atoms in many of the fragments >70 and with inter-molecular distances >10 Å. We used DFT-D3 with zero damping86-88 for dispersion correction for all functionals except the ωB97XD method, which already includes empirical dispersion correction.