Computationally Efficient Methodology for Atomic-Level Characterization of Dendrimer-Drug Complexes: A Comparison of Amine- and Acetyl-Terminated PAMAM

PAMAM dendrimers have been widely studied as a novel means for controlled drug delivery; however, computational study of dendrimer drug complexation is made difficult by the conformational flexibility of dendrimers and the nonspecific nature of the dendrimer drug interactions. Conventional protocols for studying drug binding have been designed primarily for protein substrates, and, therefore, there is a need to establish new protocols to deal with the unique aspects of dendrimers. In this work, we generate cavities in generation-5 polyamidoamine (PAMAM) dendrimers at selected distances from the center of mass of the dendrimer for the insertion of the model drug: dexamethasone 21-phosphate or Dp21. The complexes are then allowed to equilibrate with distance between centers of mass of the drug and dendrimers confined to selected ranges; the free energy of complexation is estimated by the MM-GBSA (MM, molecular mechanics; GB, generalized Born; SA, surface area) method. For both amine- and modified acetyl-terminated PAMAM at both low and neutral pH, the most favorable free energy of complexation is associated with Dp21 at distance of 15-20 angstrom from the center of mass of the dendrimer and that smaller or larger distances yield considerably weaker affinity. In agreement with experimental results, we find acetyl-terminated PAMAM at neutral pH to form the least stable complex with Dp21. The greatest affinity is seen in the case of acetyl-terminated PAMAM at low pH, which appears to be due a complex balance of different contributions, which cannot be attributed to electrostatics, van der Waals interactions, hydrogen bonds, or charge charge interactions alone.