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 Å 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.