## 3 Results and Discussion
### Molecular Dynamics Studies
#### 3.6.2 Protein-Ligand Interactions  
ER-\(\alpha\)  
To further elucidate the interactions, the protein-ligand contacts were examined. Figure 9 shows the results obtained for ER-\(\alpha\). As shown in Figure 9a, protein ligand (P-L) contacts for Pep with ER-\(\alpha\) were dominated by H-bonds and water bridges. Sites of significant H-bonding and water bridges include Glu380B, Ser463B, and Glu523D. A small number of hydrophobic interactions were also seen. A total of 20 contacts were observed on average throughout the course of the simulation (Figure 9b). For Mut1 (Figure 9c) P-L contacts were dominated by H-bonds and water bridges. Glu419D, Ser527D, and Cys417D were sites of significant H-bonding. Some hydrophobic interactions were observed, particularly at Tyr537B. The total number of contacts (Figure 9d) initially started off at an average of 24, which reduced to almost zero by the end of the simulation, which is expected based on the trajectory data that showed that the Mut1 ligand moved away from the receptor by the end of the simulation. For Mut2, the P-L interactions (Figure 9e) were dominated by H-bonds, particularly with Glu380B and Asp426B. Significant hydrophobic interactions occurred at Tyr537B, which was also indicated by PLIP. The total number of contacts throughout the course of the simulation was found to be 15 on average (Figure 9f). For Mut3, the P-L contacts (Figure 9g) are mainly H-bonds, with major interaction sites at Leu462B, Val534B, and Asp462D. Sites of hydrophobic interactions include Tyr537B and Phe461B. The total number of contacts was found to be 18, on average, with higher contacts in the initial stages of the simulation (Figure 9h). In the case of Mut4, P-L interactions (Figure 9i), show mainly H-bonds, with the highest interaction fraction being for Glu380B. Hydrophobic interactions are observed with Trp383B and Tyr537B. These results are also consistent with PLIP studies. The total number of contacts throughout the simulation was found to be 24 on average with higher contacts (30) at the 5 ns time point (Figure 9j). All of the corresponding protein-ligand atom contacts are shown in Supplementary Information Figure S8. The P-L contact histograms for the polyphenol-peptide conjugates with ER-\(\alpha\) are shown in Figure 10. For RMA-Mut1 (Figure 10a), H-bonding, particularly with Tyr537B, Asp538B, and Leu462B is observed. Residues mainly involved in hydrophobic interactions include His373B and Tyr537B. The Tyr537B residue is thus involved in both H-bonding and hydrophobic interactions. The total number of contacts (Figure 10b), on average, was found to be 10, with major dips in the number of contacts in the 20 ns and 35 ns region, after which the number of contacts remains relatively steady after 40 ns at about 10 contacts. P-L contacts for RMArep with ER-\(\alpha\) (Figure 10c) showed extensive H-bonding occurred with Glu423D, Tyr526B, and Glu380B of ER. Hydrophobic interactions were seen with Lys520D, while Glu380B and Glu423D were involved in ionic interactions. Tyr526B and Glu380B were also involved in H-bonding between RMAPep and ER-\(\alpha\), in accordance with PLIP results, while Glu423D and Lys520D were also implicated as interacting residues. The total number of contacts was found to be 22 contacts, on average, with the highest number of contacts being 30 at 40 ns (Figure 10d). The P-L contacts with GLAMut1 are shown in Figure 10e. H-bonding occurred with Lys531B, Ser536B, and Glu542B, while hydrophobic interactions were observed with Tyr526B, Leu539B. Lys531B, and Lys531B and Asn532B were additionally involved in ionic interactions. The total number of contacts, on average, (Figure 10f) was found to be 8, with the highest being 15 at the 40 ns and 65 ns range, after which the number of contacts remained steady at 8. P-L contacts (Figure 10g) between GLAMut2 and ER-\(\alpha\) showed several H-bonding interactions occurred with Ser463B, Leu462B, and Ser464B being prominent. Hydrophobic interactions were seen with Tyr537B and His373B.