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Hydration effects on the HET-s prion and amyloid-beta fibrillous aggregates, studied with three-dimensional molecular theory of solvation.

ABSTRACT: We study the thermodynamic properties of the experimental fragments of the amyloid fibril made of the HET-s prion proteins (the infectious element of the filamentous fungus Podospora anserina) and of amyloid-beta proteins (the major component of Alzheimer's disease-associated plaques) by using the three-dimensional molecular theory of solvation. The full quantitative picture of hydration effects, including the hydration thermodynamics and hydration structure around the fragments, is presented. For both the complexes, the hydration entropic effects dominate, which results in the entropic part offsetting the unfavorable energetic part of the free energy change upon the association. This is in accord with the fact that the hydrophobic cooperativity plays an essential role in the formation of amyloid fibrils. By calculating the partial molar volume of the proteins, we found that the volume change upon the association in both the systems is large and positive, with the implication that high pressure causes destabilization of the fibril. This observation is in good agreement with the recent experimental results. We also found that both the HET-s and amyloid-beta pentamers have loose intermolecular packing with voids. The three-dimensional molecular theory of solvation predicts that water molecules can be locked in the interior cavities along the fibril axis for both the HET-s and amyloid-beta proteins. We provide a detailed molecular picture of the structural water localized in the interior of the fibrils. Our results suggest that the interior hydration plays an important role in the structural stability of fibrils.

SUBMITTER: Yamazaki T

PROVIDER: S-EPMC2576381 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Hydration effects on the HET-s prion and amyloid-beta fibrillous aggregates, studied with three-dimensional molecular theory of solvation.

Yamazaki Takeshi T Blinov Nikolay N Wishart David D Kovalenko Andriy A

Biophysical journal 20080808 10

We study the thermodynamic properties of the experimental fragments of the amyloid fibril made of the HET-s prion proteins (the infectious element of the filamentous fungus Podospora anserina) and of amyloid-beta proteins (the major component of Alzheimer's disease-associated plaques) by using the three-dimensional molecular theory of solvation. The full quantitative picture of hydration effects, including the hydration thermodynamics and hydration structure around the fragments, is presented. F ...[more]

PMID: 18689456

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Project description:The HET-s prion-forming domain from the filamentous fungus Podospora anserina is gaining considerable interest since it yielded the first well-defined atomic structure of a functional amyloid fibril. This structure has been identified as a left-handed beta solenoid with a triangular hydrophobic core. To delineate the origins of the HET-s prion-forming protein and to discover other amyloid-forming proteins, we searched for all homologs of the HET-s protein in a database of protein domains and fungal genomes, using a combined application of HMM, psi-blast and pGenThreader techniques, and performed a comparative evolutionary analysis of the N-terminal alpha-helical domain and the C-terminal prion-forming domain of HET-s. By assessing the tandem evolution of both domains, we observed that the prion-forming domain is restricted to Sordariomycetes, with a marginal additional sequence homolog in Arthroderma otae as a likely case of horizontal transfer. This suggests innovation and rapid evolution of the solenoid fold in the Sordariomycetes clade. In contrast, the N-terminal domain evolves at a slower rate (in Sordariomycetes) and spans many diverse clades of fungi. We performed a full three-dimensional protein threading analysis on all identified HET-s homologs against the HET-s solenoid fold, and present detailed structural annotations for identified structural homologs to the prion-forming domain. An analysis of the physicochemical characteristics in our set of structural models indicates that the HET-s solenoid shape can be readily adopted in these homologs, but that they are all less optimized for fibril formation than the P. anserina HET-s sequence itself, due chiefly to the presence of fewer asparagine ladders and salt bridges. Our combined structural and evolutionary analysis suggests that the HET-s shape has "limited scope" for amyloidosis across the wider protein universe, compared to the 'generic' left-handed beta helix. We discuss the implications of our findings on future identification of amyloid-forming proteins sharing the solenoid fold.

Dataset Information

Hydration effects on the HET-s prion and amyloid-beta fibrillous aggregates, studied with three-dimensional molecular theory of solvation.

Publications

Hydration effects on the HET-s prion and amyloid-beta fibrillous aggregates, studied with three-dimensional molecular theory of solvation.

Similar Datasets

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