Abstract
In modeling structures with multiple conformers, the one with the higher occupancy is typically used under implicit understanding. Multiple conformers have rarely been studied to determine whether a structure with a higher ligand occupancy conformer is more stable and has stronger protein-ligand binding than the one with the lower occupancy. We performed fragment molecular orbital (FMO) calculations on complexes with high and low ligand occupancies, comparing their energies, such as total energy and ligand binding energy, to investigate this question. The structures for FMO calculation were the SARS-CoV-2 main protease (Mpro) and the covalent inhibitor, GC376. The initial X-ray crystal structure of the complex (PDB ID: 7CB7) possessed stereo isomers of GC376, namely B1S (R form) and K36 (S form), with different occupancies. Our findings showed that for all structural optimization conditions, the total energy of the high ligand occupancy B1S complex was lower than that of the low ligand occupancy K36 complex. In addition, stronger interfragment interaction energy (IFIE) of B1S than of K36 was confirmed for most structural optimization conditions. These differences between B1S and K36 are caused by the presence and absence of a hydrogen bond between the ligand and His41, as revealed by IFIE and structural geometry analyses between the ligand and each amino acid residue of Mpro. The present study, under several structural optimization conditions, would have the potential to model energetically stable structures by efficiently selecting high occupancy conformers from structures with different ones.
