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.