Based on structural and MD simulation data, we have proposed a proton-injection driven proton pumping model of complex I . In this model, for every electron transfer to Q bound at site 1, a proton originating from the N side is loaded on the proton loading site (PLS) suggested to be located at the junction of E-channel and Q-tunnel (Fig. ). One potential residue that can form part of the PLS region is the conserved aspartic acid (Asp203) from the ND1 subunit (Fig. ). Site-directed mutagenesis and simulation data speaks for the functional importance of this residue . The proton on the PLS stabilizes the anionic Q intermediate (either anionic semiquinone or anionic quinol) which diffuses to second tunnelbound Q binding (site 4, Fig. ). A back-of-the-envelope calculation suggests that a proton on PLS and an anionic Q species are stabilized by electrostatic interaction amounting to ca. 8 kcal/mol or 360 meV at ε=4 and with a distance of ~10 Å between the two. Subsequent protonation of the anionic Q intermediate at the distal site (site 4) unlatches the electrostatic coupling between the proton on PLS and the anionic Q species, resulting in the release of the PLS proton towards the membrane domain via the E channel to be pumped eventually.