Efficiency of QM/MM optimization and fragment molecular orbital calculations for investigating interactions between zinc metalloprotease and its inhibitors

In this study, we analyzed the binding characteristics of the zinc (Zn) metalloprotease pseudolysin (PLN) derived from Pseudomonas aeruginosa and its inhibitors at the electronic level to elucidate their interactions with PLN and propose novel inhibitors against PLN. A PLN contains a Zn ion in its active site, and describing the electronic states around the Zn ion accurately using conventional molecular mechanics (MM) calculations is challenging. Therefore, we applied a quantum mechanics/molecular mechanics (QM/MM) hybrid approach to optimize the structures of PLN-inhibitor complexes and verified that the structure obtained by QM/MM closely resembled the experimental one. Furthermore, using the ab initio fragment molecular orbital (FMO) method, we performed a high-precision analysis of specific interactions at the electronic level between PLN amino acid residues and each inhibitor, achieving computational results that reproduced the trend of inhibitory effectiveness observed in previous experiments. Based on the FMO results, we propose a new inhibitor with higher binding affinity for PLN, which is potentially capable of effectively inhibiting its enzymatic function.