Cavity hydration dynamics in cytochrome c oxidase and functional implications [Biophysics and Computational Biology]
Cytochrome c oxidase (CcO) is a transmembrane protein that uses the free energy of O2 reduction to generate the proton concentration gradient across the membrane. The regulation of competitive proton transfer
pathways has been established to be essential to the vectorial transport efficiency of CcO, yet the underlying mechanism at
the molecular level remains lacking. Recent studies have highlighted the potential importance of hydration-level change in
an internal cavity that connects the proton entrance channel, the site of O2 reduction, and the putative proton exit route. In this work, we use atomistic molecular dynamics simulations to investigate
the energetics and timescales associated with the volume fluctuation and hydration-level change in this central cavity. Extensive
unrestrained molecular dynamics simulations (accumulatively
μs) and free energy computations for different chemical states of CcO support a model in which the volume and hydration level
of the cavity are regulated by the protonation state of a propionate group of heme a3 and, to a lesser degree, the redox state of heme a and protonation state of Glu286. Markov-state model analysis of
μs trajectories suggests that hydration-level change occurs on the timescale of 100–200 ns before the proton-loading site is
protonated. The computed energetic and kinetic features for the cavity wetting transition suggest that reversible hydration-level
change of the cavity can indeed be a key factor that regulates the branching of proton transfer events and therefore contributes
to the vectorial efficiency of proton transport.
Publisher URL: http://www.pnas.org/content/114/42/E8830.short
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