Steered molecular dynamics studies reveal different unfolding pathways of prions from mammalian and non-mammalian species

Prion diseases are associated with an abnormal conformational transition involving the prion protein and are known to affect mammals. Here, the different mechanical behaviour of two mammalian, human (HuPrP) and Syrian hamster (ShaPrP), and two non-mammalian, chicken (ChPrP) and turtle (TuPrP), prions was assessed by steered molecular dynamics simulations performed on the globular domains of the four proteins. In mammalian prions a greater resistance to external stretching forces and an earlier occurrence of irreversible events were observed. The different unfolding pro. le of mammalian prions, ascribable to the intramolecular interactions involving helix 1 with helix 3, implicate the existence of metastable non-native states which may prompt abnormal pathways of protein misfolding and aggregation.