A tentative mechanistic proposal is provided in Figure to account for these experimental and theoretical insights (see also S194-S202). In this mechanistic proposal, the trisulfide first undergoes a reversible rearrangement to a thiosulfoxide reactive intermediate (a non-linear isomer of the trisulfide containing an S=S bond) (Figure ). Calculations indicate the thiosulfoxide is 59 kJ/mol higher in energy and therefore more reactive than the linear trisulfide (S202). The polar structure of the thiosulfoxide intermediate is expected to be more favored in polar solvents such as DMF than in non-polar solvents. The calculated charge densities of the thiosulfoxide (S201) are consistent with the polar structure suggested by the charge-separated resonance form depicted in Figure . The thiosulfoxide intermediate is proposed to then react directly with a linear trisulfide in the key biomolecular metathesis step. Two pathways are considered in Figure . In pathway A, the thiosulfoxide reacts with a linear trisulfide in a six-member ring transition state. This concerted process provides two crossover products: one linear trisulfide and another thiosulfoxide. The thiosulfoxide could then react with another trisulfide and propagate the S-S metathesis in a chain reaction. In pathway B, the thiosulfoxide is shown to react with a linear trisulfide in a 5-member ring transition state, providing two linear trisulfide crossover products. Of these pathways, our theoretical calculations suggest that pathway B is preferred and this currently serves as our working hypothesis for the mechanism of this unusual reaction. Additional mechanistic hypotheses and a summary of supporting or opposing evidence is provided in the Supporting Information (S194-S202).