## 3 Results and Discussion
### Molecular Dynamics Studies
#### 3.6.1 Analysis of RMSDs and RMSFs for Ligand-Receptor Complexes
Mut1 also attached to the hinge region; however, at 25 ns, the ligand appeared to change conformation, fold up and move slightly away from the alpha-helix adjacent to the C-lobe. The ligand remains stable for the entirety of the simulation at this position after 25 ns. The Mut2 peptide appeared to bind in the same region as well; however, during the course of the simulation, it appeared to fold up, between 50 ns and 75 ns but, by the end of the simulation, it showed binding with the alpha-helix region adjacent to the C-lobe. For the Mut3 peptide, the ligand appeared to make more contacts with the receptor, encompassing the G-loop region, as well as the alpha-helices, and further expanded and reached out to the C-lobe region during the course of the simulation. This also explains the RMSD values, showing the most stable conformation for the Mut3 peptide with EGFR. In the case of Mut4, it also bound within the hinge region and, after 25 ns, its conformation remained stable and no changes were observed, confirming that Mut4 also formed a very stable complex with the receptor. We next examined the trajectories of the polyphenol-peptide conjugates with EGFR. As shown in Supplementary Information Figure S7, for RMAPep, the ligand bound to the hinge region and encompassed the alpha-helix motif adjacent to the C-lobe. The conformation of the ligand underwent very few changes over the entire simulation process, indicating its stability once attached to the receptor. For GLAMut1, a similar result was observed, where the ligand, once attached to the receptor, underwent very few changes and remained tightly attached. In the case of RMAMut1, the ligand initially attached to the hinge region and encompassed multiple alpha-helices in the C-loop region, however, at 25 ns, the ligand appeared to flip, and the aromatic rings of the RMA moiety appeared to bind to the G-loop region and the peptide component moved toward the alpha-helices of the C-lobe. At the end of the simulation, the ligand appeared to move further inward, attaching more with the alpha-helices on the C-lobe. The trajectory of GLAMut2, however, showed a completely different story. While, initially, it appeared to be below the binding pocket, during the course of the simulation, it appeared to move inward, fold into itself, and then appeared to bind minimally to the loop region. This explains the large RMSD after 75 ns, where the ligand position changes completely as it initially moves away and then moves closer. This indicates that GLAMut2 shows relatively weak binding initially. For CGAMut4, the ligand remained attached to the binding pocket throughout the simulation process, though slight changes occurred in the conformation of the ligand. It is interesting to note however, that in the case of this ligand, after 50 ns, the ligand appeared to more toward the beta-sheet region of the N-lobe rather than the C-lobe, towards which the other ligands appeared to move. For CGAMut4, only part of the ligand binds to the G-rich loop of the cleft region, while a substantial portion of the ligand appears to bind above the cleft region. Furthermore, the ligand appeared to change conformation at the 50 ns to 75 ns range and appeared to move toward the C\(\alpha\)-helix region, though a major part of the ligand seemed to be away from the receptor. This further confirms that this particular ligand-receptor complex is relatively less stable compared to some of the other ligands, which remain tightly attached throughout the simulation process.