Ternary complexes of cyclodextrins with alkali earth cations and amino acids in gas phase investigated by mass spectrometry

Noncovalent ternary complexes between cyclodextrins (CDs), small molecules and alkali earth cations drew growing attention due to their potential application in many chemical and pharmaceutical fields. To date, the main factors affect the formation mechanism of noncovalent ternary complexes in gas phase have not been fully investigated. In this study, ternary complexes of CDs, divalent metal cations and amino acids (AAs) were investigated by electrospray ionization mass spectrometry (ESI-MS), demonstrating the formation of 1:1:1 stoichiometric noncovalent ternary complex of [CD + cation(II)+AA] 2+ in gas phase. The results revealed that only +2 valence cations can form stable ternary complexes in ESI-MS. The ratio of peak intensities for [β-CD + Mg(II)+AA] 2+ to those for [β-CD + Mg(II)] 2+ hydrophobicity of AAs was also determined to discuss the effect of hydrophobicity of AAs. Exceptions exist for Pro, Gly, and Val indicated that other factors such as side-chain structure and rigidity of AAs can also influence the binding strength for ternary complexes. Collision induced dissociations (CID) were performed to further confirm the formation of the β-CD ternary complexes, revealing the binding strength of [CD + Mg(II)+Phe] 2+ decreased in the order of γ-CD, β-CD, and α-CD. Although Leu and Ile are isomers, the ESI-MS demonstrated the peak intensity for ternary complexe of [β-CD + Mg(II)+Ile] 2+ exhibited stronger than that of [β-CD + Mg(II)+Leu] 2+ , DFT theoretical calculations were conducted to explain the phenomenon. The calculation indicated when Mg 2+ existing, the conformations of the two ternary complexes could be affected due to the electrostatic force . In the complexes, the Leu and Ile turn a way round, inserting to the cavity with their carboxylic acid side into the large rim side of β-CD and interacting with Mg 2+ . This work not only clearly explained the factors influencing the formation of [CD + cation(II)+AA] 2+ in gas phase, but it also provides an insight in designing ternary complexes for areas such as drug design and chiral discrimination.