The Design Of The Leucine Zipper Peptides And Molecular Simulation Of The Leucine Zipper Structured Thermosensitive Liposomes

Recently,due to the frequent occurrence of cancer in China,the Chinese government has offered much fund in cancer treatment to develop new cancer therapies and produce more novel anti-cancer drugs.Our lab has developed one novel thermosensitive liposomes as the drug delivery whose key component is the leucine zipper peptide.This thermosensitive liposome has great targeting ability and thermosensitivity,combining with the hyperthermia,this new drug delivery could carry anti-cancer drugs to the diseased region safely.We chose to conduct molecular dynamics simulations to research this thermosensitive liposome.On the one hand,we could decrease the development period.On the other hand,we could research this leucine zipper structured liposome in molecular level,which might offer more suggestions for the improvement of this drug delivery.This text mainly describes the application of molecular dynamics on four parts:(1)Replica exchange molecular dynamics method was applied to simulate the protein folding process.We ran 100 ns Replica exchange molecular dynamics simulation on six different leucine zipper peptides.After the dihedral principal component analysis,we got the free energy landscapes of these six leucine zipper peptides at 16 different temperatures.Then,through the DSSP method,we got the transition temperatures of these 6 leucine zipper peptides and found some laws as follows:While the carbon chain length of the leucine zippers' head groups is increased,the transition temperatures of the leucine zipper peptides would also increase.After the addition of Alanine residue and Serine residue,Tc will decrease.(2)We ran 5 ns Metadynamics to calculate the free energy of the dimers and trimers for the leucine zipper lipopeptides to judge the stability of the multimer for the leucine zipper lipopeptides.Results showed that the total free energy of trimers is close to the total free energy of dimers for the leucine zipper lipopeptides,but the single chain free energy of dimers is much less than the single chain free energy of trimers for the leucine zipper lipopeptides.So we could confirm that the stable multimer for this leucine zipper lipopeptide is the dimer structure.(3)PACKMOL was used to add leucine zipper lipopeptides into the DPPC bilayer and Amber was applied to research the properties of leucine zipper lipopeptides.We ran 50 ns conventional molecular dynamics method at 4 different temperatures to simulate this novel thermosensitive liposome.Based with the MM/GBSA method,we got the binding free energy of 6 leucine zipper lipopeptides.Then an exponential fit was given to describe a quantitative correlation between binding strengths of the lipopeptides and structural dissociations,yet providing us a fast way to predict conformation transition temperature of the lipopeptides given the knowledge of their binding free energies calculated from independent molecular dynamics simulations.(4)The ALA peptide and C3 CO peptide were chosen to added into the DPPC bilayer to have a comparison on the empty DPPC bilayer.We still used the PACKMOL and Amber to help us to do this research.We ran 50 ns conventional molecular dynamics simulations to research the properties of the DPPC bilayer.According to the analysis of the area per lipid and electron-density profile for the DPPC bilayers,we clearly understand the underlying mechanism of phase transitions of thermosensitive liposomes,thereby facilitating the development of liposomal drug delivery.