Interheme electron tunneling in cytochrome c oxidase

Abstract

Cytochrome c oxidase (CcO) is the terminal enzyme of the respiratory chain that catalyzes respiratory reduction of dioxygen (O 2 ) to water in all eukaryotes and many aerobic bacteria. CcO, and its homologs among the heme-copper oxidases, has an active site composed of an oxygen-binding heme and a copper center in the vicinity, plus another heme group that donates electrons to this site. In most oxidoreduction enzymes, electron transfer (eT) takes place by quantum-mechanical electron tunneling. Here we show by independent molecular dynamics and quantum-chemical methods that the heme-heme eT in CcO differs from the majority of cases in having an exceptionally low reorganization energy. We show that the rate of interheme eT in CcO may nevertheless be predicted by the Moser-Dutton equation if reinterpreted as the average of the eT rates between all individual atoms of the donor and acceptor weighed by the respective packing densities between them. We argue that this modification may be necessary at short donor/ acceptor distances comparable to the donor/acceptor radii.biological electron transfer | heme-copper oxidases | Moser-Dutton ruler | reorganization energy

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases

“…15,105 On the other hand, it is somewhat larger than what as been calculated for cytochromes and iron-sulphur proteins metalloproteins (38-75 kJ/mol for the oxidation of the isolated cofactor) 27,107,108 and appreciably larger than what has been obtained for intramolecular electron transfer in cytochrome c oxidase and the photosynthetic reaction centre (7-32 kJ/mol). 18,25 This is partly owing to the relative larger inner-sphere RE for copper sites than for cytochromes, partly to the presence of many charged groups around the Cu sites, needed to neutralise the large positive charge of the trinuclear T23 cluster with its neutral His ligands. Moreover, it is likely that our calculations with a nonpolarisable force field may overestimate the RE by ~35 %, 15,105,109 (i.e.…”

“…It has been used in several studies. 16,17,18,19,20,21,22,23,24,25 Several other groups have developed extensions to this theory, as well as other methods to calculate the RE at various levels of theory, including MM, QM/MM, and QM. 20,21,23,26 In particular, it has been shown that the RE in a protein can be estimated from QM or QM/MM calculations on snapshots from classical MD simulations.…”

“…It can also be seen that single-point calculations on structures optimised by other methods give inaccurate and quite erratic results. Thus, such an approach, which has been frequently used before, 15,25 is not recommended. If instead the QM/MM-2QM minimised structures are used, we can still estimate the inner-sphere contribution to the RE using the ME calculations.…”

Reductive activation of the heme iron–nitrosyl intermediate in the reaction mechanism of cytochrome c nitrite reductase: a theoretical study

“…D op is approximately 4 for the interior of a protein [88], the radius of the active site is 4 Å , and the radius of the electrondonating heme is 4.5 Å (according to the structure from [37]). The distance between the active site and the donating heme was estimated to be 9.6 Å (the distance between the two iron centers).…”

Progress and challenges in simulating and understanding electron transfer in proteins

“…The low barrier was a consequence of a low reorganization energy (0.57 eV) due to the hydrophobic environment of the protein at short range and the membrane at long range. This article discussed some discrepancies with a previously published paper reporting a very low reorganization energy (0.2 eV) on the same ET [58], highlighting the influence of computational set-ups when estimating reorganization energies from MD simulations.…”