Changing hydration level in an internal cavity modulates the proton affinity of a key glutamate in cytochrome c oxidase

Cytochrome c oxidase contributes to the transmembrane proton gradient by removing two protons from the high-pH side of the membrane each time the binuclear center active site is reduced. One proton goes to the binuclear center, whereas the other is pumped to the low-pH periplasmic space. Glutamate 2...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-11, Vol.110 (47), p.18886-18891
Main Authors: Goyal, Puja, Lu, Jianxun, Yang, Shuo, Gunner, M. R., Cui, Qiang
Format: Article
Language:English
Subjects:
Biological Sciences
Computational Biology
Crystal structure
Cytochromes
Electron Transport Complex IV - chemistry
Electrostatics
Enzymes
Glutamic Acid - chemistry
Hydration
Hydrogen
Kinetics
Models, Molecular
Molecular Dynamics Simulation
Molecules
Oxidases
Oxygen
Permittivity
Physical Sciences
Protein Conformation
Protons
Pumping
Rhodobacter sphaeroides - enzymology
Static Electricity
Water
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Summary:Cytochrome c oxidase contributes to the transmembrane proton gradient by removing two protons from the high-pH side of the membrane each time the binuclear center active site is reduced. One proton goes to the binuclear center, whereas the other is pumped to the low-pH periplasmic space. Glutamate 286 (Glu286) has been proposed to serve as a transiently deprotonated proton donor. Using unrestrained atomistic molecular dynamics simulations, we show that the size of and water distribution in the hydrophobic cavity that holds Glu286 is controlled by the protonation state of the propionic acid of heme a ₃, a group on the proton outlet pathway. Protonation of the propionate disrupts hydrogen bonding to two side chains, allowing a loop to swing open. Continuum electrostatics and atomistic free-energy perturbation calculations show that the resultant changes in hydration and electrostatic interactions lower the Glu proton affinity by at least 5 kcal/mol. These changes in the internal hydration level occur in the absence of major conformational transitions and serve to stabilize needed transient intermediates in proton transport. The trigger is not the protonation of the Glu of interest, but rather the protonation of a residue ∼10 Å away. Thus, unlike local water penetration to stabilize a new charge, this finding represents a specific role for water molecules in the protein interior, mediating proton transfers and facilitating ion transport.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1313908110