Proton transfer in the D-channel of cytochrome c oxidase modeled by a transition network approach

Determination of proton uptake pathways in Cytochrome c Oxidase is difficult due to the complexity of the system. The transition networks approach allows sampling of proton transfer pathways without predefined reaction coordinate.

Computation of the proton transfer pathways in a model of the D-channel of cytochrome c oxidase has been performed by a transition network approach that combines discrete, optimisation based and molecular dynamics based sampling.

The optimal pathway involves an opening of the so-called asparagine gate, hydration of the asparagine region, the formation of a hydrogen-bonded chain, and finally concerted proton hole transport along this chain. The optimal pathway finds the protonation of residue H26 close to the channel entrance favourable for lowering the transition energies of subsequent steps, in particular, opening of the Asn gate and formation of a hydrogen-bonded chain. Residue Y33 plays an important role in shuttling the transferred proton hole.

The optimal pathway found by the transition network approach shows the same important characteristics as pathways determined earlier by other methods. The computed barrier and reaction energies are also in good agreement with previous studies. The transition network approach provides an alternative to explore pathways in complex systems.

The correct function of the enzyme as oxidase and proton pump depends on the interplay of several redox and proton transport steps. Understanding the proton transport mechanism is therefore key to understanding the protein's function. The complex nature of long- distances proton transfer through a protein requires a non-trivial simulation strategy.