## 4 Conclusions  
In this work, we modeled the LRP1 subdomain 2 and examined its interactions with PHF Tau. Fourteen short segments containing 10 amino acids each were then designed based on the 23-amino-acid PHF binding region of the Cluster 2 subdomain of LRP1. Docking, molecular dynamics studies and clustering analysis of the trajectories revealed that of those fourteen peptides, two (TauRP (1-14) and TauRP (1-8)) showed suitable binding interactions with critical residues of PHF Tau, including Lys 353 and Lys 369 as well as Gln 351. As a proof of concept, we examined the binding interactions of Tau fibrils with the most optimal peptide (DNSDEENCES) obtained from computational studies. SPR analysis revealed that binding was significantly reduced when the Tau fibrils were pre-associated with DNSDEENCES. Additionally, CD spectra showed a change in conformation of the Tau fibrils. Flow cytometry studies confirmed that fibrillar Tau uptake was substantially reduced when pre-associated with Tau fibrils. Most importantly, it was revealed that the  
Figure 11: Flow cytometry analysis showing changes in uptake of fibrillar tau under various conditions. Red color represents LRP1-transfected cells treated with fibrillar tau. Green represents LRP1-transfected cells treated with tau fibrils in the presence of angioepp-2 and TauRP1-14 peptide. Blue represents transfected cells treated with fibrillar tau pre-associated with TauRP1-14 peptide. Orange represents untreated non-transfected cells. Tau RP1-14 (DNSDEENCES) sequence may be designed for further studies in vivo to explore its effects in mitigating tau uptake. Additionally, preliminary docking studies were conducted with A\(\beta\) (1-42) as well as the receptor-binding region of APOE4, MMP-13 and ADAMTS-4 to determine if the peptides also interact with additional LPR1 ligands. This work represents an important step forward in the use of computational tools such as docking studies and molecular dynamics to pre-screen peptides that may affect the tau-LRP1 interaction. Additionally, other receptor models that may be involved in Tau uptake can also be studied to generate short peptide sequences that may mitigate fibrillar Tau uptake. It would also be interesting to conduct further studies on short peptide segments from other regions of the ligand-binding domain of the LRP1 receptor. The following supporting information can be downloaded at [[https://www.mdpi.com/article/10.3390/app13020853/s1](https://www.mdpi.com/article/10.3390/app13020853/s1)]([https://www.mdpi.com/article/10.3390/app13020853/s1](https://www.mdpi.com/article/10.3390/app13020853/s1)), Table S1: Thread templates generated from Phyre2 with 100% confidence level that were modeled to determine the Cluster 2 subdomain structure of LRP1. Table S2: Top template threads obtained from I-TASSER studies to determine the secondary structures of the 23-amino-acid sequence of Cluster 2 domain and the fourteen designed peptides. Figure S1: Comparison of RMSDs of peptide bound complexes with PHF Tau over 100 ns simulations. Figure S2: Comparison of size and number of clusters formed for TauRP (1-2), TauRP (1-4), TauRP (1-8) and TauRP (1-14) based on clustering results obtained from the trajectory images of the last 25 ns of 100 ns MD simulations upon binding to PHF Tau calculated from the RMSD matrices. Figure S3: Protein-ligand contacts over 100 ns simulations between PHF Tau and (top row, left) TauRP (1-2) with total contacts; (top row, right) TauRP (1-4) with total contacts; (bottom row, left) TauRP (1-8) with total contacts; (bottom row, right) TauRP1-14 and total contacts. Figure S4: DLS analysis showing the formation of fibrillar Tau aggregates in the size range of 100 to 200 nm. Figure S5: Emission spectrum ThT bound to fibrillar tau aggregates at excitation of 450 nm. Conceptualization, E.J.B. and L.A.B. ; methodology, E.J.B., B.G.G. and I.A.B. ; validation, B.G.G. and I.A.B. ; formal analysis, B.G.G. and I.A.B. ; investigation, E.J.B., B.G.G., C.G.L. and I.A.B. ; data curation, E.J.B., B.G.G. and C.G.L.