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- 저자 : Huong T. D. Bui (검색결과 2 건)
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Prathit Chatterjee,Myung Keun Cho,Huong T. D. Bui,Sihyun Ham 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.8
Amyloid ? (A?) senile plaques and Tau neurofibrillary tangles (NFTs) are major hallmarks of Alzheimer's disease (AD). However, early stages of Tau aggregation are still limitedly recognized. Here, we present atomistic molecular dynamics simulations and thermodynamics characterizations of heterogeneous Tau43-A?42 and homogeneous Tau43-Tau43 dimerization processes. Two-stage approaching-accommodation mechanism after individual diffusive regime is observed. The approach step involves opposing forces driving two distant monomers to come closer to each other, which are the decrease in protein internal and water-induced energies, respectively. In the accommodation step, a decrease in protein internal energy is the main driving force for stable compact structure formation. While the charged residues differently initiate and stabilize the dimer structures, the hydrophobic residues (11VQIVYK16 in Tau43 and 39VVIA42 in A?42) facilitate the formation of compact dimers, in agreement with experiments. Our results of Tau43-A?42 and Tau43-Tau43 dimerization will illuminate early onset mechanisms of AD pathology and corresponding therapeutic initiatives.
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Prathit Chatterjee,Thi-Diem Le,Huong T. D. Bui,Myung Keun Cho,Sihyun Ham 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.8
Recent studies in Alzheimer's disease (AD) investigated the precise mechanisms responsible for neurofibrillary tangles (NFT) and senile plaques formation. NFTs, the aggregated Tau protein isoforms, are one of the primary factors behind AD. The corresponding smallest variant Tau43, as paired helical filaments (PHFs), self-assemble into pathological diseased aggregates. However, the molecular details in rationalizing the aggregation propensity of Tau43 remain elusive. Herein, using molecular dynamics simulations on aqueous Tau43, we identify the molecular factors responsible for early behavior of Tau43 aggregation propensity in water. The variant is intrinsically unstructured yet compact in nature, in agreement with previous studies. The PHF6 (11VQIVYK16) segment is relatively less fluctuating, yet most extended and hydrophobic, thereby shielded from aqueous environment by intermolecular polar interactions between terminal residues. We also compared structural propensities of Tau43 and oppositely charged A?42 peptide, providing a comparative understanding of early AD pathway, leading to corresponding drug designing avenues.
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