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- 검색키워드
- 저자 : Prathit Chatterjee (검색결과 3 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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Computer Simulations of Intrinsically Disordered Proteins
Chong, Song-Ho,Chatterjee, Prathit,Ham, Sihyun Annual Reviews 2017 Annual review of physical chemistry Vol.68 No.-
<P>The investigation of intrinsically disordered proteins (IDPs) is a new frontier in structural and molecular biology that requires a new paradigm to connect structural disorder to function. Molecular dynamics simulations and statistical thermodynamics potentially offer ideal tools for atomic-level characterizations and thermodynamic descriptions of this fascinating class of proteins that will complement experimental studies. However, IDPs display sensitivity to inaccuracies in the underlying molecular mechanics force fields. Thus, achieving an accurate structural characterization of IDPs via simulations is a challenge. It is also daunting to perform a configuration-space integration over heterogeneous structural ensembles sampled by IDPs to extract, in particular, protein configurational entropy. In this review, we summarize recent efforts devoted to the development of force fields and the critical evaluations of their performance when applied to IDPs. We also survey recent advances in computational methods for protein configurational entropy that aim to provide a thermodynamic link between structural disorder and protein activity.</P>
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