## 3 Results and Discussion
### Binding Interaction Analysis with PLIP
#### 3.5.1 Interactions with Estrogen Receptor
\(\pi\)-stacking interactions occurred between Tyr526A and Tyr537A of ER-\(\alpha\) and CGAPep. A \(\pi\)-cation interaction also occurred between Arg412D of ER-\(\alpha\) and CGAPep and a salt bridge was observed between His516D and the C-terminal of CGAPep. The results obtained for CSAAPep are shown in Supplementary Information Table S3b and Figure 3b. As shown, conjugation with carnosate led to nine hydrophobic interactions and only twelve hydrogen bonds formed. Some hydrophobic interactions that were seen for Pep were eliminated, including those with Glu423D, Thr460B, and Met522B, while new ones were formed with Asp426D, Tyr526A, Asn532A, and Val534A. New hydrogen bonds were formed in several locations, including Arg412D, Glu423D, Thr460B, Asn532A, and Val533A. While three \(\pi\)-stacking interactions occurred with Tyr526A of ER, salt bridges were absent. The GLA-Pep conjugate (Supplementary information Table S3c and Figure 3c) formed sixteen hydrogen bonds and seven hydrophobic interactions were observed in addition to one \(\pi\)-cation interaction. New hydrophobic interactions were formed with Thr465B, Tyr537A, Leu539A, Leu541A, and Glu542A. Several hydrogen bonds that were observed for Pep were eliminated, including those with Glu380B, Asp426D, Ser463B, His516D, Ser518B, and others; however, new H-bonds were observed with Arg412D, Glu423D, Phe461B, and Asn532A. For RMAPep (Figure 3d, and Supplementary Information Table S3d), eighteen hydrogen bonds and ten hydrophobic interactions were observed, and an additional \(\pi\)-stacking interaction formed between Tyr526A and RMAPep. Some hydrophobic interacting residues seen for Pep were observed, while new residues included Val422D, Leu462B, and Tyr526A. Several changes in hydrogen bonding positions were also observed, including new H-bonds with Cys381B, Trp383B, Arg412D, Met427D, Thr460B, Asn532A, Tyr537A, and Tyr537B. We next explored the binding interactions with the Mut1-polyphenol conjugates. The chlorogenate-Mut1 (CGAMut1) results are shown in Supplementary Information Table S3e and Figure 3e. Hydrogen bonds with Arg412D, Asn532A, Ser536A, and Asp538A were still observed, while others were formed with new residues, including Thr371B, Asp374B, Glu380A, Glu380B, Trp383A, Asp426D, and Val5344A, among other residues. Hydrophobic interactions were still seen with Glu423D, Tyr426A, Val534A, Tyr537A, Tyr537B, and Asp538A, while new hydrophobic interactions were seen with Asp426D, Val534A, and Glu542A. \(\pi\)-stacking occurred with Tyr526A and Tyr537B, respectively. A \(\pi\)-cation interaction occurred between His373B of ER-\(\alpha\) and CGAMut1. Results for CSAMut1 are shown in Supplementary Information Table S3f and Figure 3f. This conjugate exhibited six hydrophobic interactions and thirteen hydrogen bonds. Hydrophobic interactions with Tyr526A, Tyr537B, Asp538A, Val422C, and Lys531B were observed. One \(\pi\)-stacking interaction and one salt bridge occurred. For the gallate-Mut1 (GLAMut1) conjugate, nine hydrophobic interactions and thirteen H-bonds occurred, as shown in Supplementary Information Table S3g and Figure 3g. The H-bonds were observed with different residues compared to those seen for neat Mut1, indicating a change in position of the ligand within the receptor binding site upon conjugation with gallate. Hydrophobic interactions with Tyr526A and Tyr537B were still seen, while all others were formed with different residues, including Glu423C, Thr460A, and Met522A. \(\pi\)-stacking occurred with Tyr526B and salt bridges occurred with His516C and Lys520C. R\(\Lambda\)MAut1 (Figure 3h and Supplementary Information Table S3h) led to the formation of twenty hydrogen bonds and eleven hydrophobic interactions with ER-\(\alpha\). Many new hydrogen bonds were formed, including with His373B, Glu380A, Trp383B, Asn519B, Lys520D, Leu525A, Tyr526B, Met528A, Tyr537A, and Asp538B. Several new hydrophobic interactions occurred with Asp426D, Thr460B, and Val534B. Additionally, a \(\pi\)-stacking interaction was observed with Tyr526A.