High resolution structures have revealed continuous pathways of hydrogen bonded water molecules and amino acid residues that can sustain proton transfer in the membrane arm of complex I . Classical MD simulations on high-resolution structures of complex I have revealed that extensive hydration can occur in its membrane arm, especially if all titratable residues are modelled in their charged states. However, a more streamlined hydration pattern and in congruence with the structural water positions occurs when simulations are performed after fixing protonation states of amino acids based on pKa calculations . The hybrid QM/MM free energy simulations performed on the membrane-bound ND2 subunit suggest that protons can move horizontally (parallel to the membrane plane) in the central axis of the subunit (Fig. ) and also transfer between antiporter-like subunits in an energetically favorable manner . Interestingly, it is observed that several conserved tyrosine residues participate in this proton transfer (Fig. ). Moreover, this can occur without any substantial structural changes if there is a source (proton donor) and sink (proton acceptor), and medium (hydrated pathway with titratable and polar residues) available (Fig. ) . In coupling model discussed here, two pumped protons are taken up from the N phase via E channel for two-electron reduction of Q to QH2 (Fig. and). Therefore, the other two protons must be taken up via the antiporter-like subunits. The exit of all four pumped protons might occur from the terminal ND5 subunit (ice blue in Fig. but see section 8), a notion that was proposed originally by Sazanov and colleagues . The other two subunits ND2/4 do not display clear P side paths as in ND5, but their existence cannot be excluded. Potential P side paths in ND2/4 are marked with red dotted arrows in Fig. . We emphasise that an injected proton does not travel the entire distance from the PLS to the P-side in one catalytic cycle. It electrostatically impinges on a series of protons lined up in the hydrophilic axis (roughly half the membrane dielectric), which eventually leads to the ejection of the most advanced protons to the P-side via ND5 exit.