First-principles molecular dynamics study on the atomistic behavior of His503 in bovine cytochrome c oxidase.

We report first-principles molecular dynamics calculations based on density functional theory performed on the entrance part of the D-path pathway in bovine cytochrome c oxidase. Our models, which are extracted from the fully reduced and oxidized X-ray structures, include His503 as a protonatable site. We find that the protonated His503 with the deprotonated Asp91 [H503-N(δ1)H(+) and D91-C(γ)OO(γ)] are more energetically favorable than other protonation states, [H503-N(δ1) and D91-C(γ)OOH], with an energy difference of about -5kcal/mol in reduced case, while the [H503-N(δ1)H+ and D91-C(γ)OO(-)] state is energetically unstable, about +3kcal/mol higher in energy in the oxidized case. The local interaction of His503 with the surrounding polar residues is necessary and sufficient for determining the energetics. The redox-coupled rotation of His503 is found to change the energetics of the protonation states. We also find that this rotation is coupled with the proton transfer from His503 and Asp91, which leads to the transition between the two different protonation states. This study suggests that His503 is involved in the proton supply to the D-path as a proton acceptor and that the redox-controlled proton-transfer-coupled rotation of His503 is a key process for an effective proton supply to the D-path from water bulk. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins.

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