Structural molecular dynamics studies on polyamidoamine dendrimers for a therapeutic application: Effects of pH and generation

Extensive simulations of PAMAM dendrimer generation 2 were performed at several pH conditions with explicit water molecules, to obtain proper conditions and validity for additional simulations without explicit water. Within the range of validity, simulation without water greatly extends the size and duration of practical simulations. We investigated the effects of long-range interaction parameters such as interaction distance and dielectric constant for molecular dynamics simulations of PAMAM dendrimer without water, concluding that charged dendrimer simulation with distance-dependent dielectric constant but without cutoff distance best mimics explicit water results. Structural variations of PAMAM dendrimers were analyzed as a function of pH and dendrimer generation using MD simulations with these long-range interaction parameters. Globular and loosely compact structures at high pH (greater than or equal to10) show conservation of atom density distribution across dendrimer generations. Highly ordered extended structures at low pH (less than or equal to4) present an increasingly hollow interior as dendrimer generation grows, resulting in more open structure which provides easier access by chemical agents. By contrast, significant branch back-folding occurred at neutral pH in addition to major peripheral distribution of the terminal groups, yielding higher interior density in the intermediate radial region between the center and the maximum radius as the generation grows. Higher generation dendrimers provide a cavity surrounded by dense atom populations, producing a more stable agent carrier. Transition to high-density packing occurs between generations 4 and 5. Volume differences between neutral and low pH calculated from R-G show a dramatic increase beginning at generation 5.