| Cell Penetrating Peptides(CPPs)are a class of special short peptide carriers that have the ability to penetrate cell membranes,typically containing 5-30 amino acid residues.They can transport both small molecules and large molecules such as peptides,proteins and nucleic acids,which do not have membrane penetration ability,into living cells.Penetration of cell membranes into cells is a prerequisite for many biomolecules with intracellular targets to function,but biological membranes that act as biological barriers prevent many macromolecules from entering cells,thus greatly limiting their use in therapeutic applications.As a kind of biofilm,cell membrane is with dynamic thin-layer structure composed of protein,lipid and polysaccharide.The majority of lipids are phospholipids,which are composed of glycerol,phosphoric acid and fatty acids,and phospholipids are bipolar molecules,both hydrophilic and hydrophobic.Thus,it is an urgent problem to understand how CPP penetrate the cell membrane.This thesis studied the binding mechanism of two kinds of Pa DBS1-derived peptides with different phospholipid membranes by using coarse-grained molecular dynamics and umbrellashaped sampling,and analyzed the influence of cardiolipin concentration on the membranepenetrating mechanism of antimicrobial peptide AA139,which laid a theoretical foundation for drug design,transportation and treatment in the future.1.Binding mechanism of two Pa DBS1 derived peptides with different phospholipid membranes and its coarse-grained molecular dynamics analysisPa DBS1 is a ribosome fragment derived from archaea Pyrobaculum aerophilum.Although it has no antibacterial activity,the derived peptides Pa DBS1R1(2n9r)and Pa DBS1R6(6cfa)formed by replacing some amino acids with it show strong antibacterial activity.Base on this,using molecular dynamics simulation method of coarse granulation and umbrella sampling method,we established two phospholipid membrane models with mammalian cell membrane and Gramnegative cell membrane as templates,calculated the dynamic process and structural properties between natural peptide Pa DBS1 and other two derived peptides and different phospholipid bilayers,and analyzed the peptide-membrane interaction process from the perspectives of structural changes and forces respectively.It is shown that the contact between Pa DBS1R1(2n9r)and Pa DBS1R6(6cfa)and Gram-negative membrane mainly depends on the combination of electrostatic interaction and hydrophobic interaction,and also has a great relationship with the binding mode of phospholipid membrane,and the final result is the cell membrane is broken and die.Besides,6cfa may be more suitable as a candidate drug for the treatment of nosocomial infection caused by Gram-negative bacteria than 2n9 r.2.The effect of cardiolipin concentration on the membrane-penetrating mechanism of antimicrobial peptide AA139Arenicin peptide mainly comes from Nereis Arenicola marina,and AA139 is the analogue of Arenicin-3,a member of this Arenicin peptide family.Both arenicin-3 and AA139 have good antibacterial effects,but arenicin-3 is easy to destroy mammalian cell membranes.Firstly,we explored the dynamic process of the interaction between arenicin-3 and AA139 and Escherichia coli membrane by using the coarse-grained molecular dynamics method.Results show that the interaction between them is mainly due to electrostatic interaction and hydrophobic interaction,and AA139 has better effect than arenicin-3.Secondly,the effect of cardiolipin concentration on the membrane-penetrating process of AA139 was investigated.Through analysis,we got some conclusions.The existence of cardiolipin will lead to a certain negative intrinsic curvature of phospholipid membrane and cardiolipin has the ability to counteract the destructive effect of peptides.Meanwhile,the existence of it will also change the structure of the Escherichia coli membrane... |
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