Tau protein misfolding and aggregation induced by abnormal
N-glycosylation: Insights from Molecular dynamics simulation studies.
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.