## 3 Results and Discussion
### Molecular Dynamics Studies
In the case of the (TauRP1-2) (KAWVCDGDND) peptide ligand, it appears to be settled between the B and the J chains, making critical contacts with Lys 353, Arg 349 and Gln 351 throughout the final 25 ns of the simulation, likely due to charge interactions with the aspartic acid residues of the peptide and H-bonding interactions. For TauRP1-4, interestingly, the peptide appears to move closer to the binding pocket of PHF Tau through similar interactions as TauRP1-2. For TauRP1-8, contacts were seen with His 362, Gln 351 and Lys 369 throughout the last 25 ns of the simulation. TauRP1-14 also becomes more compactly nestled in the binding pocket as the simulation progresses, making key contacts with Lys 353, His 362, Lys 369 and Gln 351. The total number of clusters obtained for the last 25 ns of each of the TaupRP with PHF Tau is shown in Supplementary Materials Figure S2. As seen in the figure, the least number of clusters was seen for TauRP1-14 (6 clusters), while TauRP (1-4) showed the formation of the highest number of clusters (16). TauRP (1-2) and TauRP (1-8) displayed 15 clusters. This indicates that the most stable binding interactions were found to be with TauRP (1-14) due to fewer changes occurring toward the end of the simulation. The protein-ligand contacts are shown in Supplementary Materials Figure S3. As can be seen, in the case of TauRP1-2 (Figure S3a), the main contacts are with R349 of the D chain; Q351 of the B, D, F and H chains; and K353 of the H chain. The total number of contacts on average was found to be between 14 and 24, with the number of contacts showing an increase after 60 ns. The average number of contacts remained in the range of 22 to 24 after 60 ns. The highest interaction fraction (3.5) was seen with Q residue 351 at 3.5, indicating its role in stabilizing the interactions between Tau and TauRP1-2. For TauRP1-4, the number of interacting residues were found to be higher (Figure S3b), though the overall interaction fractions were found to be lower. The most significant difference observed between TauRP1-2 and TauRP1-4 interactions with PHF Tau was the increase in the number of ionic interactions with TauRP1-4, which was found to occur with K353 residue of the D, J, F and H chains of tau. Other significant interactions included H-bonds and water bridge formation with R349 of the H and J chains and with Q351 of the H chain. Overall, the total number of contacts was found to be on average 20, although around 10 ns,there was a dip in the number of contacts, after which the number of contacts remained between 16 and 20. TauRP1-8 also showed a number of ionic interactions with tau protein (Figure S3c) with K353 and K369 residues of the D, F, H and J chains. Other prominent interactions included those seen with H362, Q351 and R359, which mostly interacted through H-bonds and water bridges. The interaction fractions were higher for this peptide compared to TauRP1-4, though it was found to be lower than TauRP1-2. The number of contacts remained fairly stable throughout the simulation, with an average of 20 contacts for most of the simulation, with fewer contacts observed for the first 5 ns (10). This indicates that the position of the ligand within the binding region was altered during the simulation process such that it was able to interact more favorably in the later part of the simulation. For TauRP1-14 (Figure S3d), ionic interactions and H-bonds were seen with R349 of the B chain (which also showed the highest interaction fraction at 2.5). Ionic interactions were also seen with K353 of the D, F and H chains; K369 of the F and H chains; and K375 of the J chain. Thus, the highest number of interactions with lysine residues was seen with TauRP1-14. Like the three previous peptides, Q351 from the B, F and H chains were found to interact with TauRP-14 through H-bonds and water bridges, implying its importance in stabilizing interactions with all the peptides. The total number of contacts was also found to be highest for TauRP1-14, with an average of 30 contacts over the 100 ns simulation.