Modulating the Pro-Apoptotic Activity of Cytochrome C at a Biomimetic Electrified Liquid|Liquid Interface

Abstract

Programmed cell death via apoptosis is a natural defence against excessive cell division, crucial at all stages of life from foetal development to maintenance of homeostasis and elimination of precancerous and senescent cells.In this presentation, an electrified liquid|liquid bio-interface is demonstrated that replicates the molecular machinery of the inner mitochondrial membrane at the onset of apoptosis. By mimicking in vivo cytochrome c (Cyt c) interactions with cell membranes, our platform allows us to modulate the conformational plasticity of the protein by simply varying the electrochemical environment at an aqueous|organic interface. Our experimental findings supported by molecular modelling show that adsorption, orientation, restructuring, and pro-apoptotic peroxidase activity of Cyt c can all be precisely manipulated. Remarkably, we observe interfacial electron transfer between an organic electron donor decamethylferrocene and O2, electrocatalysed by Cyt c. This interfacial reaction requires partial Cyt c unfolding, mimicking Cyt c in vivo peroxidase activity.Our electrified liquid|liquid bio-interface motivates development of biomimetic electrochemical platforms to identify drug molecules that can potentially downregulate Cyt c and protect against uncontrolled neuronal cell death in Alzheimer’s and other neurodegenerative diseases. As proof-of-concept, we demonstrate that bifonazole, predicted to target the heme pocket, inhibits the electrocatalytic activity of Cyt c and switches off O2 reduction. Figure 1