The two cavities that have been described based on structural and simulation analysis , are shown in Figs. . One cavity originates at the NDUFS2/ND1 interface and the other at the ND3/LYRM6 interface. Both consist of conserved charged residues, and both become hydrated in MD simulations. The acidic residues at the entrance of these cavities (Glu39 from ND3 and Glu107 from NDUFS2) have been found to be catalytically important based on site-directed mutagenesis studies . The possibility of substrate proton transfer from the bulk N phase to the conserved ND3 residue Glu39 (Fig. ) via ND3/LYRM6 pathway was studied with the help of hybrid QM/MM approaches . The data also helped in explaining the potential cause behind uncoupling observed due to artificial locking of ND3 loop by covalent modification . It was proposed that locking the ND3 loop keeps the ND3/LYRM6 pathway open for substrate proton transfer in an ungated manner, resulting in Q reduction, but no proton pumping . In the mechanism discussed below, it is proposed that these pathways (Fig. ) transfer protons for Q redox chemistry and also enable the supply of pumped protons for proton injection as outlined below.