## 3 Results and Discussion
### Molecular Dynamics Studies
#### 3.6.2 Protein-Ligand Interactions
(**a**) with RMAPep conjugate (top); total contacts during the simulation with RMAPep conjugate (bottom); (**b**) with RMAMut1 conjugate (top); total contacts with RMAMut1 conjugate (bottom); (**c**) with GLAMut1 conjugate (top); total contacts with GLAMut1 (bottom); (**d**) with GLAMut2 conjugate (top); total contacts with GLAMut2 (bottom); (**e**) with CGAMut4 conjugate (top); total contacts with CGAMut4 (bottom); (**f**) with CSAMut4 conjugate (top); total contacts with CSAMut4 (bottom). EGFR  
For EGFR P-L contacts, for Pep and Mutations 1-4 (Figure 13), H-bonding interactions and salt-bridges played a major role in the binding interactions. In particular, Asp800 was found to have a very high interaction fraction in all cases. While fewer hydrophobic interactions were seen in the case of Pep (Figure 13a), relatively higher hydrophobic interactions were observed for Mut1 (Figure 13b) as expected given that the N-terminal Y is mutated to F. These interactions are seen with Phe997, Tyr998 and Leu1001 in addition to Leu844, Leu718, and Lys716, which are also involved in H-bonding. Interestingly, a new ionic interaction is observed with Lys745. For Pep, the total number of protein-ligand contacts was found to be in the average range of 16-18, while for Mut1, the average contacts for the entire simulation increased to 21. Figure 13: (**a**) Protein ligand contacts of EGFR-ligand complexes. (**a**) with Pep (top); total contacts with Pep (bottom); (**b**) with Mut1 (top); total contacts with Mut1 (bottom); (**c**) with Mut2 (top); total contacts with Mut2 (bottom); (**d**) with Mut3 (top); total contacts with Mut3 (bottom); (**e**) with Mut4 (top); total contacts with Mut4 (bottom). For Mut2 (Figure 13c), the number of contacts throughout the simulation process was lower than for Mut1 and was found to be 17. Overall, H-bond interactions were the dominant interactions, while hydrophobic interactions also played a role. No ionic interactions were observed, given that the His at position 2 of the original peptide was mutated to Ile. For Mut3 (Figure 13d), a very high interaction fraction was observed for Asp800 (4.0, highest among all the peptides). Other residues involved also showed higher interactions (between 0.7-1.0) compared to Mut1, 2 and Pep. In addition to H-bonding and water-bridges, a few hydrophobic interactions were also observed. Additionally, on average, about 22 contacts were observed throughout the simulation process. For Mut4 (Figure 13e), once again Asp800 showed a high interaction fraction due to H-bonding and water-bridges, though it was lower than that observed for Mut3. Overall, relatively lesser residues were involved in interacting. While H-bonds and water bridges were dominant, hydrophobic interactions were also seen with Leu844, Phe795, Met1002, Tyr998 and Ala722. The total number of contacts fluctuated between 24 and 16 for the first half of the simulation, though after 60 ns, the total number of contacts remained stable at an average of 20. These results indicated that in all cases the mutated peptides had higher numbers of contacts with the receptor compared to the original peptide, which may help in enhanced binding. The overall ligand atom-protein residue interactions are shown in Supplementary Interaction Figure S12, which also confirms the interactions with the various residues of the receptor. For the polyphenol-peptide conjugates, results for the protein-ligand contacts with EGFR are shown in Figure 14. For the RMA-Pep conjugate (Figure 14a), we observed a number of H-bond and water-bridge interactions, in addition to few hydrophobic interactions with Phe723, Tyr998, Leu1001, Lys716, Val717, Leu799, Arg803 and Met1002. Figure 14: Protein ligand contacts of EGFR ligand complexes.