Abstract
Geometric and electronic structure changes in the copper (Cu) centers in bilirubin oxidase (BOD) upon a four-electron reduction were investigated by quantum mechanics/molecular mechanics (QM/MM) calculations. For the QM region, the unrestricted density functional theory (UDFT) method was adopted for the open-shell system. We found new candidates of the native intermediate (NI, intermediate II) and the resting oxidized (RO) states, i.e., NIH+ and RO0. Elongations of the Cu-Cu atomic distances for the trinuclear Cu center (TNC) and very small structural changes around the type I Cu (T1Cu) were calculated as the results of a four-electron reduction. The QM/MM optimized structures are in good agreement with recent high-resolution X-ray structures. As the structural change in the TNC upon reduction was revealed to be the change in the size of the triangle spanned by the three Cu atoms of TNC, we introduced a new index (l) to characterize the specific structural change. Not only the wild-type, but also the M467Q, which mutates the amino acid residue coordinating T1Cu, were precisely analyzed in terms of their molecular orbital levels, and the optimized redox potential of T1Cu was theoretically reconfirmed.
Highlights
Bilirubin oxidase (BOD) catalyzes the bilirubin oxidation using the reduction of dioxygen into water: 2 bilirubin + O2 → 2 biliverdin + 2 H2 O
In the oxidized state such as RO0, the quantum mechanics/molecular mechanics (QM/MM) optimized T1Cu(II)-S(Met467) distance is R(T1Cu(II), The T1Cu is coordinated by four amino acid residues, His398, Cys457, His462, and Met467
S(Met467)) = 3.23 Å, which is longer compared to the other coordination distances; R(T1Cu(II), the oxidized state such as RO0, the QM/MM optimized T1Cu(II)-S(Met467) distance is R(T1Cu(II), N(His398)) = 2.01 Å, R(T1Cu(II), N(His462)) = 1.98 Å, and R(T1Cu(II), S(Cys457)) = 2.17 Å
Summary
Bilirubin oxidase (BOD) catalyzes the bilirubin oxidation using the reduction of dioxygen into water: 2 bilirubin + O2 → 2 biliverdin + 2 H2 O. BOD belongs to the family of multicopper oxidases (MCOs) which contain unique Cu atoms, i.e., type I copper (T1Cu), type II copper (T2Cu) and type. These Cu atoms have been classified based on their spectroscopic and magnetic properties [1]. BOD is a monomeric protein with a molecular mass of 60 kDa and consists of three domains [2,3]. The O2 reduction is carried out at the trinuclear Cu center (TNC), which is composed of one T2Cu and a pair of T3Cu atoms, T3aCu and T3bCu. T1Cu plays an essential role in electron
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