期刊
BULLETIN OF THE KOREAN CHEMICAL SOCIETY
卷 42, 期 8, 页码 1126-1133出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/bkcs.12334
关键词
Alzheimer's disease; Protein aggregation; Tau43 and A beta 42 proteins; Molecular dynamics simulations; Solvation thermodynamics analyses
资金
- Samsung Science and Technology Foundation [SSTF-BA1401-52]
This study reveals a two-stage mechanism of Tau43-Aβ42 and Tau43-Tau43 dimerization through atomistic molecular dynamics simulations and thermodynamics characterizations, identifying the forces driving monomers approach and formation of compact structures, as well as the roles of charged and hydrophobic residues in this process.
Amyloid beta (A beta) 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 beta 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 ((11)VQIVYK(16) in Tau43 and (39)VVIA(42) in A beta 42) facilitate the formation of compact dimers, in agreement with experiments. Our results of Tau43-A beta 42 and Tau43-Tau43 dimerization will illuminate early onset mechanisms of AD pathology and corresponding therapeutic initiatives.
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