## 3 Results and Discussion
### Binding Interaction Analysis with PLIP
#### 3.5.3 Interactions with EGFR  
PLIP results for each of the peptides docked with EGFR are shown in Figure 6 and detailed interactions are indicated in Supplementary Information Table S6. Eight hydrophobic interactions and nine hydrogen bonds were predicted, according to PLIP as shown in Figure 6a and Supplementary Information Table S6a. Mut1, as indicated in Figure 6b and Supplementary Information Table S6b, showed comparatively lower (six) hydrophobic interactions and six H-bonds, as well as a salt bridge with Lys745A. Hydrophobic interactions with Asp800A, Arg841A, and Leu844A that were seen for Pep were still observed, while new ones were formed with Leu718A and Gly719A. Hydrogen bonds with Lys745A and Asp800A were likewise maintained, while new H-bonds were seen with Met793A, Gly796A, Asp855A, and Asn996A. Mut2 (Figure 6c and Supplementary Information Table S6c) displayed eleven hydrophobic interactions and ten hydrogen bonds as well as a salt bridge with Lys745A. New hydrophobic interactions formed compared to Pep included those with Leu718A, Gly719A, Met793A, Glu804A, Thr854A, Asp855A, and Leu1001A. New hydrogen bonds included those with Leu718A, Ser720A, Met793A, Asn842A, Thr854A, Asp855A, and Asn996A. Mut3, as seen in Figure 6d and Supplementary Information Table S6d exhibited only two hydrophobic interactions and five hydrogen bonds while for Mut4, six hydrophobic interactions and four hydrogen bonds were predicted, along with a salt bridge with Asp800A, as shown in Figure 6e and Supplementary Information Table S6e. Hydrophobic interactions occurred with Val726A, Leu844A, and Leu1001A, while H-bonds were shown with Lys745A, Arg803A, Asp855A, and Lys913A. PLIP results for polyphenol-peptide conjugates are shown in Figure 7 and Supplementary Information Table S7. For CGA-Pep, as shown in Figure 7a and Supplementary Information Table S7, six hydrophobic interactions and eight hydrogen bonds occurred, one \(\pi\)-cation interaction with Arg803A was seen. Some hydrophobic interactions seen for Pep alone were maintained, including those with Leu799A, and Asp800A, while new ones were formed with Ser720A, Ala722A, Val876A, and Pro877A. H-bonds with Asp800A and Arg803A were still seen, while new ones were seen with Gly719A, Ser720A, Gly721A, Cys797A, Arg841A, and Val876A. As indicated in Figure 7b and Supplementary Information Table S7b, eight hydrophobic interactions and seven hydrogen bonds were formed for CSA-Pep. Compared to Pep alone, new hydrophobic interactions were seen with Ser720A, Thr854A, Trp880A, and Lys913A. New hydrogen bonds were observed with Val717A, Leu718A, Ser720A, and Cys797A. GLA-Pep (Figure 7c and Supplementary Information Table S7c) displayed only six hydrophobic interactions and six hydrogen bonds, in addition to one \(\pi\)-cation interaction with Arg841A. The RMAPep conjugate (Figure 7d and Supplementary Information Table S7d) however showed increased interactions comparatively (nine hydrophobic) and ten hydrogen bonds. Figure 6: PLIP results for each of the peptides bound to EGFR receptor. (**a**) Original peptide; (**b**) Mut1 (**c**) Mut2 (**d**) Mut3 (**e**) Mut4. CGAMut1, as shown in Figure 7e and Supplementary Information Table S7e, displayed hydrophobic interactions with Ser720A, Val726A, Asp855A, Trp880A, and Lys913A, while new hydrogen bonds were seen with Leu718A, Ser720A, Ala722A, Gly724A, Arg803A, Arg841A, Lys913A, and Asp916A. No interactions observed for Mut1 alone were maintained, indicating a change of position within the EGFR binding site. The CSAMut1 conjugate displayed increased interactions (fifteen hydrophobic interactions and ten hydrogen bonds) as shown in Figure 7f and Supplementary Information Table S7f. Compared to Mut alone, several new hydrophobic interactions and H-bonds were seen. GLA-Mut1 showed lower interactions (eight hydrophobic interactions, nine hydrogen bonds). However, two \(\pi\)-stacking interactions with Trp880A, and one \(\pi\)-cation interaction with Arg841A were observed, as shown in Figure 7g and Supplementary Information Table S7g.