The conformational analysis of artemisinin by molecular dynamics and quantum chemistry calculations revealed the existence of seven energy minima with specific interconversion pathways. Among the seven conformers, only Atm1, 2 and 5 were able to undergo bond rearrangements upon Fe2+ interaction. These rearrangements were due to a peculiar puckering of the trioxane ring that brings its three oxygen atoms in an ideal geometrical position for interacting with Fe2+ ions, promoting an electronic redistribution in the molecule. A rapid molecule rearrangement led to a stable energy minimum structure with an additional ring that is similar to a plant metabolite. Our results suggest an alternative pathway for generating toxic radical chemical species for the malaria parasite, where artemisinin is not toxic by itself but rather is an intermediate for molecular partners that generate radical structures deleterious for the parasite proteins, after electron transfers from the Fe2+/artemisinin complex.
