Atomic Level Investigations of Early Aggregation of Tau43 in Water I. Conformational Propensity of Monomeric Tau43

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 Aβ42 peptide, providing a comparative understanding of early AD pathway, leading to corresponding drug designing avenues. Molecular dynamics simulations have been undertaken to investigate early aggregation mechanism (responsible for Alzheimer's disease aggregates) of the Tau43 isoform. It is inherently unstructured yet compact, agreeing with experiments. The critically aggregating PHF6 (6VQIVYK11) segment is conformationally less fluctuating, more extended and more hydrophobic. Also Tau43 is compared with corresponding conformational propensity of existing Aβ42 ensemble.