| Cell-penetrating peptides are a kind of polypeptide that composed of 5-30 amino acids.It can not only across the membrane,but also can carry proteins,nucleic acids and liposomes into the cell membrane to play a role.Therefore,cell-penetrating peptides have great research significance in tumor targeting therapy and improve drug absorption rate.The antibacterial activity center of bovine lactoferrin is BLFcin6,and its sequence is RRWQWR,which has strong antibacterial penetrating activity,but loses the ability of anti-cancer cells,and is also a cell-penetrating peptide.BLFcin6 via a Glycine-Glycine linker to hepta-arginine generate a new cell-penetrating peptide derivative.It is called MPLfcinB6 that has selectively cytotoxic for human T-leukemia and B-lymphoma cells.BLFcin6 and its derivative MPLfcinB6 are expected to become new tumor target penetrating peptide.However,there are still many problems to be further discussed about their antibacterial penetrating mechanisms.Molecular dynamics simulation as a powerful tool to explore the life phenomenon,is an important way to deeply understand its antibacterial penetrating mechanisms.In this manuscript,the molecular dynamics simulation were used to study the interaction between BLFcin6 and five different membranes.For five kinds of cell membranes,the peptide combined with the surface of DPPC-CHOL membrane and POPG membrane rapidly;and tend to entered the hydrophobic interior of DPPC membrane.However,the peptide have little contact with POPC-CHOL membrane and POPC membrane.In terms of interaction energy,the peptide and POPG membrane have the strongest interaction,which mainly arise through the electrostatic interaction between the pepetide and the negative charge head group of cell membrane.For peptide and DPPC membrane,the interaction are mainly arise between the peptide and the hydrophobic tail of DPPC membrane.However,the peptide only combined with the surface of DPPC-CHOL membrane because of the effects of cholesterol.In the process of combination,the N-terminal Argnine residues contact with the cell membrane firstly,electrostatic interaction plays a key role in the process of peptide anchor in the cell membrane.In addition,molecular dynamics simulation were used to calculate the interaction between MPLfcin B6 and DPPC-CHOL membrane and POPC-CHOL membrane.Simulation results show that the MPLfcinB6 contact the DPPC-CHOL membrane,but not entered into the membrane,and MPLfcinB6 was far from the POPC-CHOL membrane.Computing the distance between the MPLfcin B6 different amino acid residues and different membranes centroid,found that the C-terminal antimicrobial activity center(BLFcin6)was closer than the N-terminal,and Argnine plays an important role in the peptide-membranes interaction.The above research analysed the interaction mechanisms between BLFcin6 and MPLfcinB6 and diffrent cell membranes at the atomic level,which are the key residues,and also provide help for the further transmembrane study of BLFcin6 peptide and MPLfcin B6 peptide.In addition,MPLfcinB6 is a tumor target peptide,it can not only reduce the adverse reactions of anti-tumor drugs,but also improve the utilization rate of drugs,which has important research significance in tumor targeted treatment.Because of the conventional molecular dynamics simulation,the sampling time is limited and the sampling efficiency is low,we did not observe the transmembrane processes of BLFcin6 and MPLfcin B6.Therefore,it is necessary to further study whether BLFcin6 and MPLfcin B6 can penetrate different phospholipid membranes and the specific transmembrane process.In order to solve these problems,we can use Metadynamics and its variants to enhance the sampling and improve the sampling efficiency.In addition,we can build a mixed phospholipid membrane containing DPPC,POPE,POPS and cholesterol to make it closer to the cell membrane in physiological environment,and then make the peptides more easily to penetrate the membranes. |
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