Syringol has an additional methoxy group in comparison to guaiacol, and it can not be demethylated by the WT-P450GcoA enzyme. Interestingly, unlike the enzyme in presence of guaiacol that displays mainly the closed conformation, the WT enzyme in presence of syringol shows an open conformation of the substrate access channel during entire MD simulations (SI Fig S1 and) and is consistent with the previous literature. Therefore, we propose that syringol may act as an allosteric modulator that triggers the channel opening in the WT P450GcoA enzyme. To validate this allosteric effect, we carefully monitored the interaction of the syringol with nearby protein residues and found that the distal methoxy carbon of syringol favorably interacts with the π electron clouds of the F169 residue via C-H-π and C-H-O interactions (Figure ). Since F169 belongs to the substrate access channel, the interaction of the syringol with F169 triggers the conformation of the substrate access channel changed from a closed to an open state. The open doorway allows water influx to access Cpd I (Figure ) and is in contrast with the previous simulations where there were no water molecules found near the Cpd I. However, similar to guaiacol, syringol also forms a strong hydrogen bond with the backbone oxygen of V241 which stabilizes syringol in the binding site.