Substrate binding-dissociation and intermolecular electron transfer in cytochrome c oxidase are driven by energy-dependent conformational changes in the enzyme and substrate

• Published in: Biotechnology and applied biochemistry 2012-05, Vol.59 (3), p.213-222
• Main Authors: Ashe, Damian, Alleyne, Trevor, Sampson, Valerie
• Format: Article
• Language: English
• Subjects: Binding Sites; Biological and medical sciences; Biotechnology; Computational Biology; conformational changes; cytochrome c; cytochrome c oxidase; Electron Transport; Electron Transport Complex IV - metabolism; Energy Transfer; Fundamental and applied biological sciences. Psychology; non-local energy; Oxidation-Reduction; Protein Binding; Protein Conformation; salt bridges; solvent accessibility; Substrate Specificity
• ISSN: 0885-4513; 1470-8744
• DOI: 10.1002/bab.1015

Reduction of O2 by cytochrome c oxidase (COX) is critical to the cellular production of adenosine‐5′‐triphosphate; COX obtains the four electrons required for this process from ferrocytochrome c. The COX–cytochrome c enzyme–substrate complex is stabilized by electrostatic interactions via carboxylates on COX and lysines on cytochrome c. Conformational changes are believed to play a role in ferrocytochrome c oxidation and release and in rapid intramolecular transfer of electrons within COX, but the details are unclear. To gather specific information about the extent and relevance of conformational changes, we performed bioinformatics studies using the published structures of both proteins. For both proteins, we studied the surface accessibility and energy, as a function of the proteins' oxidation state. The residues of reduced cytochrome c showed greater surface accessibility and were at a higher energy than those of the oxidized cytochrome c. Also, most residues of the core subunits (I, II, and III) of COX showed low accessibility, ∼35%, and compared to the oxidized subunits, the reduced subunits had higher energies. We concluded that substrate binding and dissociation is modulated by specific redox‐dependent conformational changes. We further conclude that high energy and structural relaxation of reduced cytochrome c and core COX subunits drive their rapid electron transfer.