Recently, the atomistic details of the electronic wiring of seven Fe/S clusters (N3, N1b, N4, N5, N6a, N6b, N2) of respiratory complex I, along which electrons are injected into the electron transport chain, have been revealed; the tunneling pathways between the clusters and the contributing key residues were identified [1]. In this study, the sensitivity of the electron tunneling pathways to the internal water at the protein subunit boundaries is investigated by simulating tunneling pathways of N3 -> N1b and N6b -> N2 with and without the internal water. It is found that the hydrogen bonding networks formed along the internal water provide new efficient tunneling pathways. In N3 -> N1b, the tunneling pathway with the internal water is drastically different with a significantly shorter (3.4 angstrom) total tunneling distance along the trajectory. In N6b -> N2, the internal water contributes to the tunneling as a bridge between N6b and (9)Ile(99) with two shorter through-space jumps instead of one longer jump. The resulting enhancement of the rates of the individual electron tunneling process is two to three orders of magnitude. This study demonstrates that the tunneling pathways and tunneling rates are sensitive to the internal water, suggesting that the tunneling pathways change dynamically due to the water diffusion and the efficient electron tunneling occurs at the optimal positions of the internal water molecules. (C) 2011 Elsevier B.V. All rights reserved.