Abstract
The conformational change from the cellular prion protein (PrPc) to scrapie prion protein (PrPsc) is a key process in prion diseases. The prion protein has buried water molecules which significantly contribute to the stability of the protein; however, there has been no report investigating the influence on the buried hydration sites by a pathogenic mutation not adjacent to the buried hydration sites. Here, we perform molecular dynamics simulations of wild type (WT) PrPc and pathogenic point mutant T188R to investigate conformational changes and the buried hydration sites. In WT-PrPc, four buried hydration sites are identified by residence time and rotational relaxation analysis. However, there are no stable buried hydration sites in one of T188R simulations, which indicates that T188R sometimes makes the buried hydration sites fragile. We also find that fluctuations of subdomains S1-H1-S2 and H1-H2 increase in T188R when the buried hydration sites become unstable. Since the side chain of arginine which is replaced from threonine in T188R is larger than of threonine, the side chain cannot be embedded in the protein, which is one of the causes of the instability of subdomains. These results show correlations between the buried hydration sites and the mutation which is far from them, and provide a possible explanation for the instability by mutation.
Highlights
Prion diseases, including Creutzfeldt-Jakob disease and mad cow disease, are one of the neurodegenerative diseases caused by aggregation of misfolding proteins.[1]
Later analysis were conducted using the data after equilibrium, which accounts for totally 800 ns simulation data for wild type (WT)-PrPc and T188R
Performing molecular dynamics (MD) simulations of WT-PrPc and T188R, we found the following two key points. (i) T188R mutation affects secondary structure leading to the increase of β-sheet content and the decrease of helix 2. (ii) the mutation point is located far from the buried hydration sites, the sites become unstable by the mutation
Summary
Prion diseases, including Creutzfeldt-Jakob disease and mad cow disease, are one of the neurodegenerative diseases caused by aggregation of misfolding proteins.[1] The prion protein is a causal protein for prion diseases and its dynamics has attracted researchers’ interests for elucidating prion diseases. The prion diseases are composed of mainly three processes: (i) conformational change of secondary structure, (ii) aggregation of transformed prion proteins, and (iii) accumulation of protein amyloids on nerve cells. Conformational change and aggregation of prion proteins are quite important because they may be related to the mechanism of Alzheimer’s disease and Parkinson disease.[2,3] these processes remain an unresolved biological phenomena.
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