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Tau protein misfolding and aggregation induced by abnormal N-glycosylation: Insights from Molecular dynamics simulation studies.
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  • Alen Mathew T,
  • Anurag Baidya TK,
  • Bhanuranjan Das,
  • Bharti Devi,
  • Rajnish Kumar
Alen Mathew T
Indian Institute of Technology BHU Varanasi

Corresponding Author:[email protected]

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Anurag Baidya TK
Indian Institute of Technology BHU Varanasi
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Bhanuranjan Das
Indian Institute of Technology BHU Varanasi
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Bharti Devi
Indian Institute of Technology BHU Varanasi
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Rajnish Kumar
Indian Institute of Technology BHU Varanasi
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Abstract

Various post translational modifications like hyper phosphorylation, O-GlycNAcylation, 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 microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359residue 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 tend 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&Lys370 helped maintaining the stability of the protein in the folded state.
30 Jun 2022Submitted to PROTEINS: Structure, Function, and Bioinformatics
04 Jul 2022Submission Checks Completed
04 Jul 2022Assigned to Editor
22 Jul 2022Reviewer(s) Assigned
07 Aug 2022Review(s) Completed, Editorial Evaluation Pending
08 Aug 2022Editorial Decision: Revise Major
18 Aug 20221st Revision Received
19 Aug 2022Submission Checks Completed
19 Aug 2022Assigned to Editor
19 Aug 2022Reviewer(s) Assigned
19 Aug 2022Review(s) Completed, Editorial Evaluation Pending
23 Aug 2022Editorial Decision: Accept