Fig. 5: Molecular simulations of compounds (R)- and (S)-4a with ShHTL7.
The key residues around the binding pocket are shown as blue sticks and the hydrogen-bonding interactions are shown as black dashed lines. a Docking models of (R)-4a to ShHTL7, there were two reasonable binding modes: Conf1 (shown in yellow stick) and Conf2 (shown as green stick). b Docking model of (S)-4a to ShHTL7, (S)-4a is shown as magentas sticks. c–e Binding models of (R)-4a (conf1), (R)-4a (conf2), and (S)-4a to ShHTL7, respectively. The models were taken from the last frame of each simulation at 1000 ns. f A schematic description of the hydrolysis reaction of the catalytic triad. D5′C-OG, DNE2-HG, DOD1-HD1, and DOD2-HD1 were used as a set of geometry parameters to describe the privileged conformation (PC) of ligands and ShHTL7. g A process to predict the privileged conformation of (R)- and (S)-4a with ShHL7 based on the MD simulations and conformational distribution statistical analysis. h A proposed alternative schematic diagram of the ShHTL7-mediated (S)-4a hydrolysis pathway. The hydrogen-bonding interactions of Thr157 and 2O atom, and Tyr174 and 3O atom could activate the leaving group, and the catalytic process begins with the nucleophilic attack by the NE2 atom of His246 to the 2′C atom of (S)-4a, which results in the C5H5O2 modification of His246.
