Figure 1.

An illustration of the catalytically preferred binding mode of compound 1b, “Mode I”, after molecular dynamics equilibration in preparation for EVB simulations. (A) An overview of the AMDase binding pocket. (B) A detailed overview of the interactions between the substrate and oxyanion hole. (C) A detailed overview of substrate positioning in the hydrophobic pocket. The corresponding amino acids main chains are for simplicity excluded from the figure. As can be seen, after initial equilibration, the substrate rotates slightly compared to the initial docking pose (Figure S1) such that the pro-(S) carboxylate group of the substrate is stabilized by the dioxyanion hole, and the pro-(R) carboxylate group points toward the hydrophobic pocket. The initial docking poses for both Mode I and Mode II prior to equilibration are shown in Figure S1. We note that compound 1b is selected merely for illustration purposes, and similar binding modes were obtained for all compounds studied in this work.