Geometry Optimization using the Frozen Domain and Partial Dimer Approach with the Fragment Molecular Orbital Method: Implementation, Benchmark, and Application for Ligand-Binding Site of Proteins

The frozen domain (FD) approximation with fragment molecular orbital (FMO) method is efficient for partial geometry optimization of large systems. We implemented the FD formulation (FD and frozen domain dimer [FDD] methods) already proposed by Fedorov, D. G. et al. (J. Phys. Chem. Lett. 2011, 2 (4), 282–288.); proposed a variation of it, namely frozen domain and partial dimer (FDPD) method; and applied it to several protein-ligand complexes. The computational time for geometry optimization at the FDPD/HF/6-31G* level for the active site (six fragments) of the largest β2-adrenergic G protein-coupled receptor (440 residues) was almost half that of the conventional partial geometry optimization method. In the human estrogen receptor, the crystal structure was refined by FDPD geometry optimization of estradiol, surrounding hydrogen-bonded residues and a water molecule. The rather polarized ligand binding site of influenza virus neuraminidase was also optimized by FDPD optimization, which relaxed steric repulsion around the ligand in the crystal structure and optimized hydrogen bonding. For Serine-Threonine Kinase Pim1 and six inhibitors, the structures of the ligand binding site, Lys67, Glu121, Arg122, and benzofuranone ring and indole/azaindole ring of the ligand, were optimized at FDPD/HF/6-31G* and the ligand binding energy was estimated at the FMO-MP2/6-31G* level. As a result, the correlation coefficient between pIC50 and ligand binding energy was considerably improved as compared to results from both molecular mechanics- and quantum mechanics/molecular mechanics-optimized geometries. Thus, this approach is promising as a high-precision structure refinement method for structure-based drug discovery.