Molecules, Vol. 28, Pages 4545: The Motion Paradigm of Pre-Dock Zearalenone Hydrolase Predictions with Molecular Dynamics and the Docking Phase with Umbrella Sampling (Molecules)

Zearalenone (ZEN) is one of the most prevalent estrogenic mycotoxins, is produced mainly by the Fusarium family of fungi, and poses a risk to the health of animals. Zearalenone hydrolase (ZHD) is an important enzyme capable of degrading ZEN into a non-toxic compound. Although previous research has investigated the catalytic mechanism of ZHD, information on its dynamic interaction with ZEN remains unknown. This study aimed to develop a pipeline for identifying the allosteric pathway of ZHD. Using an identity analysis, we identified hub genes whose sequences can generalize a set of sequences in a protein family. We then utilized a neural relational inference (NRI) model to identify the allosteric pathway of the protein throughout the entire molecular dynamics simulation. The production run lasted 1 microsecond, and we analyzed residues 139–222 for the allosteric pathway using the NRI model. We found that the cap domain of the protein opened up during catalysis, resembling a hemostatic tape. We used umbrella sampling to simulate the dynamic docking phase of the ligand–protein complex and found that the protein took on a square sandwich shape. Our energy analysis, using both molecular mechanics/Poisson–Boltzmann (Generalized-Born) surface area (MMPBSA) and Potential Mean Force (PMF) analysis, showed discrepancies, with scores of −8.45 kcal/mol and −1.95 kcal/mol, respectively. MMPBSA, however, obtained a similar score to that of a previous report.