Evaluation of Penetration Efficiency of BR۲ Peptide in Breast Cancer cell Lines Using computational Methods

Cancer remains one of the most significant health challenges of the ۲۱st century, impacting millions of individuals globally each year. BR۲ is a penetration peptide derived from the antimicrobial peptide Buforin II. Experimental evidence indicates that BR۲ exhibits approximately four times greater transfer efficiency to cancer cell lines compared to non-malignant cell lines. While the selective permeability of cell-penetrating peptides (CPPs) has been established, the precise mechanisms of internalization remain unclear. Notably, the lipid composition of cancer cell membranes differs significantly from that of non-malignant cells, with further variations observed among different types of malignant cells. Plasma membrane asymmetry is an important feature of normal cells, where phosphatidylserine is located almost exclusively in the inner leaflet of the cell membrane. In many malignant cells, this asymmetry of the plasma membrane is lost, and as a result phosphatidylserine is located in the outer leaflet of the membrane. In this study, we aim to investigate the effects of BR۲ on three distinct cell lines derived from both malignant and non-malignant breast tissues, while also exploring the mechanisms underlying its permeation. To achieve this, we employed molecular dynamics simulations using GROMACS, CHARMM GUI, and Grace software. The three-dimensional structure of BR۲ was modeled using the I-TASSER server. In this study, we utilized analysis of hydrogen binding, average peptide and membrane distance, density, radius of gyration, RMSF, RMSD, mean square deviation and order parameter. By comparing the graphs obtained from the analysis conducted, including hydrogen binding and distance measurements in selected membranes, significant results were achieved regarding the mechanism of peptide penetration. Our results demonstrate that the interaction and penetration of BR۲ in cancer cell lines are significantly more pronounced than in normal cell lines. Furthermore, our analysis suggests that the mechanism of penetration is closely related to the abundance of phosphatidylserine (PS) in the lipidome of cellular membranes. This research contributes to a deeper understanding of the selective permeability of BR۲ in varying cellular environments, which may have important implications for the development of targeted therapeutic strategies.

کلیدواژه ها:

Cell penetration peptides(CPP) ، Lipodome ، molecular dynamics simulation ، breast cancer ، Bufforin