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Developing means to characterise SARS-CoV-2 and its new variants is critical for future outbreaks. SARS-CoV-2 spike proteins have peripheral disulfide bonds (S–S), which are common in all spike proteins of SARS-CoV-2 variants, in other types of coronaviruses (e.g., SARS-CoV and MERS-CoV) and are likely to be present in future coronaviruses. Here, we demonstrate that S–S bonds in the spike S1 protein of SARS-CoV-2 react with gold (Au) and silicon (Si) electrodes. Bonding to Si is induced by a spontaneous electrochemical reaction that involves oxidation of Si–H and the reduction of the S–S bonds. The reaction of the spike protein with Au enabled single-molecule protein circuits, by connecting the spike S1 protein between two Au nano-electrodes using the scanning tunnelling microscopy-break junction (STM-BJ) technique. The conductance of a single spike S1 protein was surprisingly high and ranged …