We use monodisperse
dendrons that allow control over functional
group presentation to investigate the influence of the location of
a ligand on protein-induced disassembly and release of encapsulated
small molecules. Based on both experiments and molecular dynamics
simulations, we demonstrate that ligand location greatly influences
release of guest molecules from the dendron-based supramolecular assembly.
We show that a ligand moiety grafted to the dendron periphery is more
accessible for the target protein in aqueous solution. On the other
hand, the ligand moiety placed at the focal point or at the intermediate
layer within the dendritic scaffold is less accessible, since it is
surrounded by an environment rich in PEG chains, which hinders binding
and even influences nonspecific interactions. We also demonstrate
that the specific binding between one ligand and the target protein
can destabilize the dendritic assembly. Furthermore, if more ligands
are available, multivalent interactions are also possible with extravidin,
which speed up disassembly and trigger the release of hydrophobic
guests.
The macrocyclic ligand DO2A (1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)) was prepared and used as a building block for four new macrocyclic ligands having mixed side-chain chelating groups. These ligands and their complexes with Mg(II), Ca(II), and Ln(III) were studied extensively by potentiometry, high-resolution NMR, and water proton relaxivity measurements. The protonation constants of all compounds compared well with those of other cyclen-based macrocyclic ligands. All Ca(II) complexes were found to be more stable than the corresponding Mg(II) complexes. Trends for the stabilities of the Ln(III) complexes are discussed and compared with literature data, incorporating the effects of water coordination numbers, Ln(III) contraction, and the nature of the side chains and the steric hindrance between them. (1)H NMR titrations of DO2A revealed that the first and second protonations take place preferentially at the secondary ring nitrogens, while the third and fourth involved protonation of the acetates. (17)O NMR shifts showed that the DyDO2A(+) complex had two inner-sphere water molecules. Water proton spin-lattice relaxation rates for the GdDO2A(+) complex were also consistent with water exchange between bulk water and two inner-sphere Gd(III) coordination positions. Upon formation of the diamagnetic complexes of DO2A (Ca(II), Mg(II), La(III), and Lu(III)), all of the macrocyclic ring protons became nonequivalent due to slow conformational rearrangements, while the signals for the acetate CH(2) protons remained a singlet.
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