In the minor conformational basin, the enzyme-substrate complex shows an open conformation of the substrate access channel. In this conformation, F169 and F395 move apart so as to open the water doorway and allow the water influx (Figure ). The simulations performed by Mallinson et al. also indicate the movement of F169 and F395 due to open conformation, however there was no influx of water in the active site. The increased water influx exerts a pressure that changes guaiacol orientations which, in turn, pushes the methoxy group away from the oxygen atom of Fe (IV)=O complex. The different water accumulations in major and minor conformations are substantiated by radial distribution functions shown in SI Figure . In summary, an array of the triad residues F169 and F395 in association with water inflow regulates the substrate orientation and hence regulates the guaiacol activity.