Unveiling the novel characteristics of IGPD polymer and inhibitors binding affinities using 12-6-4 LJ-type nonbonded Mn2+ model

Abstract The metalloenzyme imidazole glycerophosphate dehydratase (IGPD) (EC 4.2.1.19) is essential in the histidine biosynthesis pathway in prokaryotes and eukaryotes, hence it has been identified as an attractive target with a majority of inhibitor studies focused on the development of broad-spectrum herbicides and bacteriostatic agent. However, due to the lack of work in structural biology, the reported inhibitors developed slowly with poor selectivity and diversity. To reveal the inhibitors binding affinities in ions centers of IGPD, we built point charge models based on a 12-6-4 type Lennard-Jones (LJ) potential, while combined DFT analyses, molecular docking and molecular dynamics (MD) simulations. This work introduced the interaction with surrounding solvent molecules and revealed a few undiscovered structural and kinetic characterizations of IGPD Mn2+ ions centers and ligand binding path, which revised some previous inexact assumptions inferred from crystal structures information. In addition, we also compared the dynamic binding characteristics of five IGPD inhibitors, and found that hydrogen bond interaction, spatial position and coordination stability with two Mn2+ ions can lead to the difference in potency. Overall, this work firstly unraveled the dynamic characteristics of IGPD polymer systems in explicit solvent and also provided a reference for the theoretical work of Mn2+-containing metalloenzyme, contributing for further target development.