## 3 Results and Discussion
### Molecular Docking Studies
#### 3.4.2. Docking Studies with Additional Ligands Implicated in Alzheimer's Disease  
Because LRP1 is known to be a versatile receptor that has an affinity toward a variety of ligands [96], we also explored the binding interactions of the four designed peptides TauRP1-2, TauRP1-4, TauRP1-8 and TauRP1-14 with common LRP1 ligands including MMP13 (collagenase), ADAMTS-4 and APOE4. All of these ligands also play a role in Alzheimer's disease, either inducing inflammatory processes [97; 98] or in the internalization or clearance of beta-amyloid peptides [99]. Therefore, we also examined if the peptides interacted with A\(\beta\) (1-42). The results are given in Figure 5. In the case of MMP-13 (Figure 5a), for all four designed peptides, docking studies revealed that binding occurred primarily with hydrophobic and neutral residues, including N173, F86, A65 and P87, as well as Y155, except in the case of TauRP1-4, where a basic residue (H166) was involved. Because the binding sites appear to differ and no Lys residues are involved, competitive interaction with PHF-Tau is not expected. We also examined interactions of ADAMTS-4 (Figure 5b), which is a metalloprotease that recognizes A\(\beta\) sequence and facilitates the formation of A\(\beta\)4-x-truncated peptides commonly formed in the [PERSON]'s diseased brain [100]. The results showed that binding interactions of the TauRP peptides occurred within the binding pocket of ADAMTS-4, with the peptides making key interactions with residues such as M332, T329, D334 and A333. Interactions were also seen with P393, M395 and H371. These results indicate that it is likely that the peptides interact with ADAMTS-4, with some key interactions such as that seen for the inhibitors of ADAMTS-4 such as hydantoin [58]. However, further studies beyond the scope of this manuscript would be needed to explore those effects on ADAMTS-4. Since the binding pocket interactions did not involve lysine residues, it appears that interference with PHF Tau binding is unlikely. We also explored interactions of the peptides with ApoE4. It is well known that ApoE4 and soluble A\(\beta\) compete for LRP1-mediated uptake in astrocytes and that ApoE influences soluble A\(\beta\) metabolism [101]. In previous studies, it has been shown that ApoE residues from the receptor-binding domain ranging from residues 130 to 149, including residues E131, E132, V135, A138 and K143, bind to the cysteine-rich complements, such as the repeat  
Figure 4: Results obtained from docking studies showing the best binding modes for (**a**) TauRP1-2 (mode 6); (**b**) TauRP1-4 (mode1); (**c**) TauRP1-4 (mode 2); (**d**) TauRP1-8 (mode 3); (**e**) TauRP1-4 (mode 2) with PHF Tau. IV region of the LRP1 region [102]. As shown in Figure 5c, TauRP1-2 appears to bind to R112, G105, D65 and Q58 residues, spanning multiple alpha helices of ApoE4. TauRP1-4, on the other hand, interacts with residues including K72, R25, A29 and A102, while TauRP1-8 interacts with E109, D65, A102 and R205. TauRP1-14 also interacts with A102 and D65, in addition to E109 and K146. Thus, it is likely that the peptides Tau RP1-14, TauRP1-4 and Tau RP1-8 may be able to bind to ApoE4 as well; however, further experimental studies would need to be conducted to examine if there would be any net effect in terms of sterol absorption or A\(\beta\) interactions with ApoE4. Because ApoE4 mainly binds through the Cluster 4 domain of LPR1, it appears to be unlikely that there would be an effect as the peptides derived in this work are obtained from the Cluster 2 domain of LRP1. Figure 5d shows the binding interactions of the docked peptides with A\(\beta\) (1-42). As can be seen, A\(\beta\) (1-42) binds to TauRP (1-2) primarily through residues including S26, G25, A21 and F20 through H-bonding and hydrophobic interactions, while all the other peptides show interactions with K28 and residues such as E22, F19, V24, G29, I31 and N27.