Journal
BULLETIN OF THE KOREAN CHEMICAL SOCIETY
Volume 42, Issue 8, Pages 1134-1142Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/bkcs.12338
Keywords
Alzheimer's disease; Protein aggregation; Tau43 protein; Molecular dynamics simulations; Conformational propensity
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Funding
- Samsung Science and Technology Foundation [SSTF-BA1401-52]
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Recent research in Alzheimer's disease has focused on understanding the mechanisms behind the formation of neurofibrillary tangles and senile plaques, particularly the role of the Tau protein. Molecular dynamics simulations have helped identify factors responsible for the aggregation propensity of Tau43, shedding light on potential drug design avenues for early AD treatment.
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 ((11)VQIVYK(16)) 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 beta 42 peptide, providing a comparative understanding of early AD pathway, leading to corresponding drug designing avenues.
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