## 1 Introduction
In a recent study, [PERSON] and co-workers demonstrated that LRP1 had a high affinity toward the microtubule-binding domain of tau and internalized tau isoforms rapidly, which was then degraded by lysosomes. Furthermore, LRP1-expressing cells also showed lysosomal escape of post-translationally modified tau and promoted cytosolic seeding of tau, thus implying different uptake mechanisms due to changes in conformation [29]. The LRP1 receptor belongs to the LDLR family, and comprises five domains [30]. The extracellular \(\alpha\)-chain contains four clusters (CCRs1 through 4) comprising complement-like repeats and EGF-like domains. Specifically, CCR2 and CCR4 contain 8 and 11 complement-like repeats (CRs) and have been shown to be involved in a majority of the ligand-binding activity [31; 32; 33], while CCR1 and CCR3 play a lesser role in ligand binding [34]. Recently, it was shown that the molecular chaperone RAP (receptor-associated protein) forms a complex with LRP1 through vital lysine residues present on RAP, which are critical for binding to complement repeat domains of LRP1 [35; 36]. In a separate study, docking studies of ribosome-inactivating proteins alpha-momorcharin (\(\alpha\)-MMC), trichosanthin (TCS) and Momordica anti-HIV protein (MAP30) with LRP1 revealed strong interactions with complement repeat CR56 subunit of Cluster 2 and CR17 subunit of Cluster 3 domains of LRP1 [37]. In this work, we sought to determine if short peptide sequences derived from LRP1 ectodomain could potentially be utilized for binding to paired helical fragments of Tau and mitigate its internalization into LRP1-expressed cells. As the crystal structure of LRP1 protein remains unsolved, we determined the structure of its Cluster 2 (CCR2) via homology modeling. Homology modeling has been used extensively to predict the 3D structures of proteins and is regarded as one the most accurate methods of protein structure prediction [38]. It has been used to predict the structures of proteins, including SARS-CoV [39], umami receptor T1R1/T1R3 [40] and many rhodopsin structures [41]. We first determined the structure of LRP1 Cluster 2 (CCR2) domain via homology modeling. The site of interaction between the homology-modeled region of LRP1 and the paired helical filament (PHF) (PDB ID: 503L) [42] of tau protein was then determined. The results showed that tau interacted with a 23-amino-acid segment (SKAWVCDGDNDCEDNSEDSENCES) of LRP1 containing cysteine-rich complement-type domain of CR 3-10 region in Cluster 2 (CCR2), particularly making critical interactions with complement-type repeat 9 (CR9) region containing the segment DNDCEDNSDEE (residues 1128-1138). In previous studies, it has been shown that CR9, specifically GDNDSEDNSDEENNC (residues 1127-1140) are also critical for LRP1-mediated internalization of aggregates of LDL (agLDL) [43]. We then designed fourteen different short peptide sequences each containing 10-amino-acid residue peptides from sections of the 23-amino-acid sequence of the LRP1 Cluster 2 (CCR2) to examine binding interactions with tau. Docking studies were first conducted with the 14 peptides. Seven of those peptides which showed binding interactions with PHF Tau were subjected to additional blind docking with increased exhaustiveness. We then conducted molecular dynamics (MD) simulations of four of the peptide sequences that showed optimal binding with PHF Tau. The sequences are referred to as (a) TauRP1-2 (KAWVCDGDND), (b) TauRP1-4 (WVCDGDNDCE), (c) TauRP1-8 (GDNDCENDSD) and (d) TauRP1-14 (DNSDEENCES) that showed optimal binding. Of the four peptide sequences, TauRP1-14 (DNSDEENCES) showed the most stable binding according to MD simulations. Therefore, it was selected for further laboratory analysis as a proof of concept. Binding interactions of the sequence DNSDEENCES (Tau RP1-14) with fibrillar tau were examined using circular dichroism (CD) spectroscopy. CD studies showed that the peptide caused tau to change its conformation, forming a relatively more disordered structure.