Coarse-grained Simulations Of The Interactions Between PAMAMD Dendrimers And Biomembranes

In this dissertation, interactions between dendrimers and lipid membranes were investigated using coarse-grained molecular dynamics simulation. Dendrimers are a new class of synthetic polymer nanodevices with well-defined hyperbranched struc-tures. Recently, dendrimers have received a great deal of attention from many re-searchers because of their potential applications in the field of nanomedicine for drug and gene/DNA delivery. Poly(amidoamine) PAMAM dendrimers has been used in medical applications as multifunctional nanodevices due to their unique high homo-geneity. Since these nanodevices approach a living animal cell, they have to be effec-tively internalized by cellular plasma membranes to release therapeutic cargos inside the cell, so understanding the interaction of dendrimers with biological membranes is of central importance for both the design of effective delivery vehicles for medical applications and for avoiding unwanted side effects from destruction of cell functions.Coarse-grained molecular dynamics simulations were carried out to investigate the interactions of PAMAM dendrimers of generation7,8, and9with negatively charged bilayers. We find that the configurations of high-generation dendrimers only show a very slight change during the simulations. Furthermore, a raft-like domain com-posed of DMPG lipids occurs as the mixed bilayer gradually wraps the high-generation dendrimers, which means that the dendrimers can induce the redistribution of the com-ponents on the membranes. On the other hand, for the pure DMPG bilayer with defects, the higher the dendrimer generation is, the faster the lipids are removed from the bi-layer due to the stronger electrostatic attraction, and the larger the preexisted pore will be enlarged. Moreover, we find that the defect in our simulations is responsible for the formation of a dendrimer-encased vesicle in company with the lipid flipping and dendrimer rotation. The size and lipid number of the vesicle were found in good agree-ment with experimental results. Our simulations suggest that for the high-generation dendrimers, it is acceptable that the removal mechanism of lipids was interpreted with the dendrimer-encased vesicle model.We performed a systematic coarse-grained molecular dynamics simulations to study interactions between PAMAM dendrimers, from the3rd to the7th generation, and negatively charged gel versus fluid phase bilayers. We find that the the7th gen-eration dendrimer, G7, can fluidize the gel-phase membranes in the vicinity of the dendrimer without disturbing the lipids far away. Significant bending of the mem-brane was observed, while the projected area of the membrane kept constant during the simulation. G3dendrimer was found to flatten on the gel-phase bilayer without any disturbance on the lipids, while G4dendrimer can fluidize the upper leaflet of the membrane. The bilayer can only be fluidized by dendrimers larger than G4locally. The fluidization of lipids facilitates the aggregation of the negatively charged lipids to form DMPG-rich domains. All the results were compared with interactions between dendrimers and fluid-phase membranes. Our simulations suggest that high-generation dendrimers are much more effective in disturbing biomembranes not only at high tem-perature but also at low temperature. Our research are directly relevant to ways by which the dendrimer interact with lipid bilayers in gel and fluid phase, which are im-portant to understand the binding and internalization mechanisms of nanopaticles into cells involving lipid rafts and endocytosis.Finally, interactions of G5dendrimer and DMPG membranes were simulated us-ing the coarse-grained force field. A single G5dendrimer, which consists of either a hydrophilic or a strong hydrophobic core, was simulated with an anionic lipid mem-brane. For the dendrimer with a hydrophilic core, the dendrimer can bend the mem-brane slightly due to the electrostatic interactions between dendrimer terminals and lipid phosphates. For the dendrimer with a hydrophobic core, lipids can penetrate the dendrimer core due to the strong hydrophobic interactions between the dendrimer core and lipid tails. These simulation results shows that interactions of the dendrimer with lipid membranes are significantly modulated by dendrimer hydrophilic/hydrophobic property. Interactions of multiple copies of positively charged G5dendrimers and DMPG bilayers were simulated. We find that cationic dendrimers do not aggregate, but separate from each other due to the electrostatic repulsive-force among dendrimers. The membranes interacting with dendrimers of higher concentration are significantly deformed, no matter the dendrimer core is hydrophilic or hydrophobic. For the den-drimer with a hydrophobic core, the dendrimer can insert into the hydrophobic core of the membrane, meanwhile, the lipids also can penetrate into the dendrimer core to form dendrimer-filled micelles. We point out that the G5dendrimers act in a coopera-tive fashion when interacting with lipid membranes. Our results can give a explanation why significant material leakage was observed only at a much higher concentration for G5dendrimers. Our simulation results are helpful to guide the synthesis of dendrimers with desired properties for future medical applications.We give an introduction of the current studies on PAMAM dendrimers in Chapter1and the MARTINI force field in Chapter2. In Chapter3, we focus on the interac-tions of G7, G8, and G9PAMAM dendrimers with two kinds of negatively charged membranes. In Chapter4, we mainly focus on the interactions between PAMAM den-drimers with a gel-phase bilayer composed of DMPC and DMPG via CG MD sim-ulations within the framework of the MARTINI force field. In Chapter5, we study the effects of dendrimer hydrophobicity and concentration on the interaction between dendrimers and membranes. Conclusions and outlook are made in Chapter6.