Abstract
BackgroundProtein misfolding is the main cause of a group of fatal neurodegenerative diseases in humans and animals. In particular, in Prion-related diseases the normal cellular form of the Prion Protein PrP (PrPC) is converted into the infectious PrPSc through a conformational process during which it acquires a high β-sheet content. Doppel is a protein that shares a similar native fold, but lacks the scrapie isoform. Understanding the molecular determinants of these different behaviours is important both for biomedical and biophysical research.ResultsIn this paper, the dynamical and energetic properties of the two proteins in solution is comparatively analyzed by means of long time scale explicit solvent, all-atom molecular dynamics in different temperature conditions. The trajectories are analyzed by means of a recently introduced energy decomposition approach (Tiana et al, Prot. Sci. 2004) aimed at identifying the key residues for the stabilization and folding of the protein. Our analysis shows that Prion and Doppel have two different cores stabilizing the native state and that the relative contribution of the nucleus to the global stability of the protein for Doppel is sensitively higher than for PrP. Moreover, under misfolding conditions the Doppel core is conserved, while the energy stabilization network of PrP is disrupted.ConclusionThese observations suggest that different sequences can share similar native topology with different stabilizing interactions and that the sequences of the Prion and Doppel proteins may have diverged under different evolutionary constraints resulting in different folding and stabilization mechanisms.
Highlights
Protein misfolding is the main cause of a group of fatal neurodegenerative diseases in humans and animals
In this paper, the dynamical and energetic properties of the two proteins in solution is comparatively analyzed by means of long time scale explicit solvent, all-atom molecular dynamics in different temperature conditions
Our analysis shows that Prion and Doppel have two different cores stabilizing the native state and that the relative contribution of the nucleus to the global stability of the protein for Doppel is sensitively higher than for Prion proteins (PrP)
Summary
Protein misfolding is the main cause of a group of fatal neurodegenerative diseases in humans and animals. In Prion-related diseases the normal cellular form of the Prion Protein PrP (PrPC) is converted into the infectious PrPSc through a conformational process during which it acquires a high β-sheet content. The molecular determinants of neurodegenerative diseases have been the subject of very intense research over recent years [1,2] Particular attention in this field has been devoted to Prion proteins (PrP) due to their fundamental role as infective agents in diseases generally known as Transmissible Spongiform Encephalopathies (TSE) that affect humans and animals, including. Prion Protein (PrPC) can undergo a conformational change of the native state leading to a new isoform designated PrPSc which is insoluble, characterized by an increased content in β-structure and with a high tendency to form amyloid aggregates [5,6]. More than 20 mutations distributed throughout the sequence of PrP have been shown to lead to neurological disorders: their role has been suggested to be connected with either the lowering of the free-energy barrier in the conformational conversion favoring the formation of PrPSc, or with an increase in the oligomerization rate of the insoluble isoforms [8]
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