Structural Elucidation of Specific Noncovalent Association of Folic Acid with Native Cyclodextrins Using an Ion Mobility Mass Spectrometry and Theoretical Approach

Abstract

The combination of ion mobility mass spectrometry studies and theoretical calculations including docking studies permitted a detailed structural description of noncovalent complexes of folic acid (FA) and native cyclodextrins (α-CD, β-CD, and γ-CD). The mode of noncovalent association depended on the cavity size of the cyclodextrin. The structure of FA/α-CD represented the exclusion complex in which the aminobenzoic moiety and the aromatic pteridine ring of folic acid remain outside the cyclodextrin cavity, while the glutamate residue is anchored in the interior of the α-cyclodextrin. A rotaxane-type structure was proposed for the FA/β-CD complex with the aminobenzoic part of FA being trapped in the central cavity of β-CD. The glutamate residue and the aromatic pteridine ring interact with the primary and secondary rim hydroxyl residues, respectively, enhancing complex stability. Two possible structures of FA/γ-CD were suggested, the first one being analogous to the FA/β-CD complex and the second one being more stable-in which the aromatic pteridine ring penetrates into the CD cavity while the glutamate residue with the aminobenzoic part of FA is exposed to the cone exterior of CD at its wider edge. Further insight into the association behavior of the folic acid toward cyclodextrins evaluated by thermodynamic calculations indicates that the process is highly exothermic. The complex stability increased in the order FA/α-CD < FA/β-CD < FA/γ-CD. This order is consistent with the previously determined relative gas-phase stability established based on the dissociation efficiency curves of the FA/CD complexes.

Dynamic Formation of Noncovalent Calixsalen Aggregates

“…Figure 2 shows the superimposed IM spectra of [2 M +H] + ions of calixalens 1 – 4 . The experimental collision cross section values ( Ω exp ) of analyzed dimers, given in Table 1, were obtained by utilizing a well‐documented calibration procedure 16. 19…”

Specific Noncovalent Association of Chiral Large‐Ring Hexaimines: Ion Mobility Mass Spectrometry and PM7 Study

“…Applications of IM-MS include structural and conformationalc haracterizationo fo ligonucleotides, [12] carbohydrates, [13] lipids, [14] proteins, [15] supramolecular assemblies such as cyclodextrin-coumaric acid complexes, [16] 18-crown-6-and alanine-based polypeptide complexes, [17] chaperonin complexes, [18] an organometallic ruthenium anticancer complex and its adducts with aD NA oligonucleotide, [19] and noncovalentm olecular associationsb etween folic acida nd the native cyclodextrins a-CD, b-CD, and g-CD. [20] Recently,w edemonstrated the use of IM-MS supported by semiempirical theoretical calculations in combination with DOSY NMR ando ptical rotation( OR) measurementsf or exact determination of the structure of noncovalenta ggregateso f calixsalens 1 (Figure 1), [21] vaselike chiral macrocycles obtained through [3+ +3] cyclocondensation between enantiomerically pure trans-1,2-diaminocyclohexane and various5 -substituted 2-hydroxyisophthaldehydes. [22][23][24] The thermodynamically controlled cycloimination reactionb etween structurally predisposed diamine (donor) and dialdehyde( acceptor) is ac onvenient syntheticm ethod providing symmetrical,c hiral macrocycles resembling polygons.…”

Structural Elucidation of β‐Lactam Diastereoisomers through Ion Mobility Mass Spectrometry Studies and Theoretical Calculations

“…The IM‐MS is widely used in structural characterization of isomeric species from diverse fields of research. Currently, the IM‐MS is exploited extensively in the investigation of such biologically relevant (macro)molecules as oligonucleotides, carbohydrates, lipids, proteins and structural description of non‐covalent complexes such as chaperonin complexes and non‐covalent molecular association between folic acid and the native cyclodextrins …”

“…Currently, the IM-MS is exploited extensively in the investigation of such biologically relevant (macro)molecules as oligonucleotides, [14] carbohydrates, [15] lipids, [16] proteins [17] and structural description of non-covalent complexes such as chaperonin complexes [18] and non-covalent molecular association between folic acid and the native cyclodextrins. [19] In this work, we used the IM-MS method and theoretical calculations to separate and fully characterize six diastereoisomeric β-lactams shown in Scheme 1. The aim of the study was to determine the effect of the configuration at carbon atoms of examined βlactams on the conformational changes and mobilities of β-lactam ions using IM-MS, with the assistance of theoretical calculations.…”