Molecular dynamics and electronic structure insights into chloroquine, quercetin, and luteolin binding to HPV-16 E2 protein.

Human papillomavirus type 16 (HPV-16) E2 protein has key roles in the control of viral DNA replication. Small, biocompatible ligands with known antiviral activity and acceptable toxicity that bind to E2 and slightly change its motion may disturb these functions. In this study, we used 100 ns molecular dynamics simulations together with electronic-structure calculations to investigate how chloroquine, quercetin, and luteolin interact with E2. Analysis of protein motion (RMSD, Rg, and RMSF) showed that the protein remained stable, but ligand binding was linked to changes in the flexibility of residues near DNA-binding and other functional regions. All three ligands remained mainly near these regions during the simulations. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis supported stable binding, with quercetin showing the strongest estimated affinity. The HOMO-LUMO values and global reactivity descriptors were similar for the ligands, which may help explain their ability to settle in similar regions of E2. These findings suggest that the three ligands can influence functional areas of E2 and may indicate possible synergistic effects against protein-driven viral activity.