Results & Discussion
MD simulations are now recognized as reliable computational chemistry tool which helps in predicting atomistic movements of small biomolecules like proteins and help in understanding various biological phenomenon like protein folding, misfolding, protein stabilities, allosteric modulation and aggregation. MD simulations offer various advantages that help us model biomolecules in a predefined system having user-defined conditions of pH, ionic concentration, and temperature and predict the molecular behavior using classical mechanics. At the same time, the reliability of the results depends on the timescale of the simulation, trajectory analysis and type of simulation performed [32, 33]. In the present study we tried to explore the effects that N-glycosylation of Asn359 residue have on the tau protein dynamics using one microsecond length all atom molecular dynamics simulation. The Asn359 residue, where N-glycosylation takes place, is located within the R4 domain (repeat domain) of the microtubule binding region of tau protein [34]. Therefore, the presence of sugars in this region can sterically hinder Tau ability to bind microtubules leading to enhanced misfolding and neurodegenerative effects. Moreover, Asn359 is part of the β7 (356SLDNITHV363) region of Tau, which is one of the eight sheets (β1–β8) which form the β-core (V306–F378) of the Tau filament [35]. We chose to study the region of tau from residue 340 to 380 which include the entire B7 region and R4 repeat domain (337-369). Subjecting only the 41 amino acid long chain of tau for microsecond long molecular dynamics simulation helps to capture most of the conformational ensemble the protein can occupy, which is not the case with simulating the whole protein. Two systems were generated, Tau_plane – having only the selected residues with no modifications and Tau_glyc – having N glycosylation at Asn- 359. Since the selected region of tau has two important phosphorylation sites, i.e. Ser356 and Ser352, we choose to model separate phosphorylated systems of tau in order to compare the effects induced by both phosphorylation and by N-glycosylation [36]. Details of the different systems generated for the study are given in the methods section.