Factors Controlling the Complex Architecture of Native and Modified Cyclodextrins with Dipeptide (Z-Glu-Tyr) Studied by Microcalorimetry and NMR Spectroscopy: Critical Effects of Peripheral Bis-trimethylamination and Cavity Size

Complex stability constant (K), standard free energy (ΔG°), reaction enthalpy (ΔH°), and entropy change (TΔS°) for 1:1 inclusion complexation of the diastereomeric dipeptides Z-d/l-Glu-l-Tyr (Z = benzyloxycarbonyl) and its component amino acids (Z-d/l-Glu and N-Ac-Tyr) with native α-, β-, and γ-cyclodextrins (CDs) and A,X-modified bis(6-trimethylammonio-6-deoxy)-β-CDs (AX-TMA2-β-CDs) were determined in buffer solution (pH 6.9) at T = 298.15 K by isothermal titration microcalorimetry. Concurrent NMR spectral examinations revealed that the penetration mode and the resulting complex architecture are dramatically altered by the peripheral modification and also by the CD's cavity size. Upon complexation of the ditopic Z-Glu-Tyr guest, native α- and β-CDs preferentially bind the Z's phenyl group, whereas AX-TMA2-β-CDs predominantly include the Tyr's phenol moiety. In contrast, native γ-CD includes both of the aromatic moieties simultaneously in the same cavity. Furthermore, for isomeric AB-, AC, and AD-TMA2-β-C...