Residue Interaction Network (RIN) Analysis
Structural analysis of the lowest energy conformation of Tau_plane showed that it is having 1 salt bridge and 17 strong hydrogen bonds, while that of Tau_glyc have 2 salt bridges and 23 strong hydrogen bonds. These interactions might be helping in the stabilization of the confirmations, but we do not know which are the functionally important residues helping in folding /aggregation or maintaining the stability of the confirmation.
Residue interaction network (RIN) is an analysis tool that make use of the mathematical concept of graph theory, in which the 3D protein structures are represented as a set of nodes and edges. Here nodes represent the amino acids while the edges represent the interactions between the amino acids, creating a network [53, 54]. This network topology can be analyzed with help of various centrality measures and helps identify structurally and functionally important nodes and edges [55]. It has been used in studying protein stability and folding, effects of mutations on protein structure, protein dynamics, allosteric regulations, identification of functionally and biologically important residues, identification of ligand binding sites etc. [56-60]. Here we make use of RIN to study the functionally important residues. In order to make interaction networks, we made use of the lowest energy conformations of Tau_plane and Tau_glyc obtained from the free energy landscape analysis. The residue interaction networks are plotted inFigure S6 in supporting information, & topological analysis of the networks is done using various centrality measures like betweenness centrality (BC) and closeness centrality (CC) [61]
Betweenness centrality measure how many times a particular node acts as a bridge between the shortest path between two other nodes. It is a measure of how important a residue is in the communication of signals within a protein. Residues which have high BC reveal locations which are important for controlling the inter domain communication [62]. Vendruscolo and coworkers have previously demonstrated that residues having high BC values are found in the native structure and/or the transition state ensemble of proteins, which they identified as key residues which can initiate the folding process [63]. BC of Tau_plane and Tau_glyc were calculated and normalized Z score-based plotted in Figure 5 A.