The Transmembrane Mechanism Of Glycosyl-Phosphatidylinositol Drug And Nanopaticles

The realization of many cell functions including signal transduetion, membrane transport and cell fusion require sorts of molecules and material across membrane. Recently, from the aspects of size, shape, hydrophobic property of biological molecules, the transmembrane mechanism has been extensively studied using the computer simulation method and the adopted bilayer membrane mostly consists of pure and saturated phospholipids. However, in the real human, there are transmembrane proteins, sugars and cholesterols in the phospholipid membrane, which would change the properties of membrane, especially the stiffness. The influences of stiffness on the transmembrane mechanism of biological molecules are less studied. In order to close to the real life, the paper mainly uses the all atom molecular dynamics method GROMACS to systematically research the interaction between biological molecules including glycosylphosphatidylinositol (GPI), drug doxorubin, and nanoparticle C60 with phospholipid membrane of different stiffness (purely soft DPPC membrane and relatively stiff DPPC membrane with cholesterols). We discuss the motion and transmembrane mechanism of biological molecules with different shape at the micro level. The main contents and conclusions are as follows:(1) Glycosyl-phosphatidylinositol (GPI) containing carbohydrates and hydrophobic alkyl chain is a connector of protein and phospholipid membrane, having the biological functions of the signal transduction from one side of the biological membrane to the other. If the tails of GPI are unable to insert into membrane properly, some diseases would be caused. The paper shows the hydrophobic tails of GPI are similar to the phospholipid. The molecular process of our simulation and the calculation of free energy indicate that GPI molecule could not penetrate into the pure DPPC membrane spontaneously and need to overcome an energy barrier. But for the membrane with cholesterols the spontaneous insertion would happen in a short time. In order to achieve the anchoring function, the small anchor molecular GPI are more like to stay in the stiff area of the membrane.(2) Doxorubin is a type of hydrophobic anticancer drugs that widely used in clinical. However, its curative effect is reduced as the drug would be trapped in the membrane and difficult to arrive at the position of the cancer cell. We simulated the interactions between the hydrophobic drug and the phospholipid membrane, which are found to be sensitive to the stiff membrane with cholesterols and close to perpendicular to the X-Y plane of phospholipid membrane eventually. For the soft phospholipid membrane, the penetration and stable structure of drug molecule are in a random orientation. Meanwhile, the stiff phospholipid membrane would lengthen the time for drug molecules inserting into the membrane. We speculate that the stiff phospholipid membrane would further hold back the drug molecule in the membrane and this observation is consistent with the experimental result.(3) The third part of paper researched the interaction of nanoparticle C60 with membrane. The occurrence of nanoparticle C60 "jumping" into DPPC membrane with cholesterols is asserted as DPPC membrane, but it needs more time. The stiffness of membrane would cause lengthening of penetrating time, and the nanoparticle C60 also could jump into the membrane as the result of hydrophobic interaction instantaneously. Meanwhile, the motion trajectory of nanoparticle C60 in the DPPC membrane with cholesterols is cage-like which illustrate the adjacent phospholipids and cholesterols put a strong constraint on the movement of nanoparticle C60.