Exploring
the Possible Role of Glu286 in C<i>c</i>O by Electrostatic
Energy Computations Combined with Molecular
Dynamics
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Abstract
Cytochrome <i>c</i> oxidase (C<i>c</i>O) is
a central enzyme in aerobic life catalyzing the conversion of molecular
oxygen to water and utilizing the chemical energy to pump protons
and establish an electrochemical gradient. Despite intense research,
it is not understood how C<i>c</i>O achieves unidirectional
proton transport and avoids short circuiting the proton pump. Within
this work, we analyzed the potential role of Glu286 as a proton valve.
We performed unconstrained MD simulations of C<i>c</i>O
with an explicit membrane for up to 80 ns. Those MD simulations revealed
that deprotonated Glu286 (Glu286-) is repelled by the negatively charged
propionic acid PRD of heme a<sub>3</sub>. Thus, it destabilizes a
potential linear chain of waters in the hydrophobic cavity connecting
Glu286 with PRD and the binuclear center (BNC). Conversely, protonated
Glu286 (Glu286H) may remain in an upward position (oriented toward
PRD) and can stabilize the connecting linear water chain in the hydrophobic
cavity. We calculated the p<i>K</i><sub>a</sub> of Glu286
under physiological conditions to be above 12, but this value decreases
to about 9 under increased water accessibility of Glu286. The latter
value is in accordance with experimental measurements. In the time
course of MD simulation, we also observed conformations where Glu286
bridges between water molecules located on both sides (the D channel
being connected to the N side and the hydrophobic cavity), which might
lead to proton backflow