Prion versus doppel protein misfolding: new insights from replica-exchange molecular dynamics simulations

The doppel (Dpl) and prion (PrP) proteins share a very similar fold (three helices and two short β-strands), while they differ significantly in sequence (only 25% homologous) and in disease-related β-rich conformations that occur for PrP only. In a previous study [Baillod, P., et al. (2012) Biochemistry 51, 9891-9899], we investigated the misfolding and rare, β-rich folds of monomeric PrP with replica-exchange molecular dynamics (REMD) simulations. In the work presented here, we perform analogous simulations for Dpl with the aim of comparing the two systems and characterizing possible specificities of PrP for misfolding and amyloidogenesis. Our extensive simulations, which allow us to overcome high energy barriers via the REMD approach, sample several β-rich folds, some of which are stable at room temperature, for both proteins. Per residue secondary structure propensities reveal that novel β-sheets of Dpl and PrP are formed by amino acids belonging to the helices that are the least stable in the respective native structure, H1 for Dpl and H2 and H3 for PrP, in agreement with experimental data. Using a specific clustering method that allows discrimination against different β-strand arrangements, seven β-rich folds could be characterized for PrP and five for Dpl, which are clearly distinct and share only one single similar fold. A major difference between the two proteins is found in the free energy barriers leading to misfolded structures: they are approximately 3 times higher for Dpl than for PrP. This suggests that the difference in amyloidogenic behavior between PrP and Dpl might be due to kinetic reasons.