Prediction of the binding modes between macrolactin N and peptide deformylase from Staphylococcus aureus by molecular docking and molecular dynamics simulations

Abstract

Macrolactin N is a novel lactone compound against Staphylococcus aureus peptide deformylase (PDF) with an IC50 value of 7.5 μM, while its binding mode with PDF still remains largely unknown. In this study, the binding mechanism of macrolactin N to PDF was investigated using molecular docking, molecular dynamics (MD) simulations, and free energy calculations. Four typical binding modes were obtained by FlexX docking and cluster analysis, which are named as Model A, Model B, Model C, and Model D. The predicted binding free energy of Model A is more stable than those of the other three models. Besides, the free energy decomposition and structure analysis, as well as the hydrogen bond occupancy analysis further demonstrate that Model A is the most appropriate conformation for ligand binding. We found that the Zn2+ ion in Model A has positive contribution with the ligand, which implies the introduction of a metal chelating functional group on this model could further improve the binding affinity to PDF. The feasibility of the results of our molecular docking and MD simulation work was examined by the result about PDF-actinonin in terms of the theoretical simulation and the experimental results (e.g., crystal structure). Meanwhile, four predicted binding modes are validated by means of comparing their binding modes with actinonin, and the comparison result shows that the macrolactin N in Model A may have the highest similarity to the binding mode of actinonin. This work might be useful in designing more promising PDF inhibitors.