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

Abstract

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.

NOE analysis using dual injection DNP‐NMR for studies of solvent–solute interactions at low concentrations

“…Observations of NOE signals from 1 H in water to heteronuclei such as 13 C or 19 F in target molecules have facilitated the calculation of heteronuclear cross‐relaxation rates, serving as indicators of the proximity between water and target molecules and revealing interaction sites. Water plays an important role in protein function and structure, 6,7 making water–protein interactions an intriguing subject for studies using NOEs 8–10 …”

“…5 Observations of NOE signals from 1 H in water to heteronuclei such as 13 C or 19 F in target molecules have facilitated the calculation of heteronuclear cross-relaxation rates, serving as indicators of the proximity between water and target molecules and revealing interaction sites. Water plays an important role in protein function and structure, 6,7 making water-protein interactions an intriguing subject for studies using NOEs. [8][9][10] However, the primary drawback of these measurements is the low sensitivity of NOE signals arising from water, which are typically changes of only a few percent in the signal intensity of a target spin.…”