False positives and the detection of cyclodextrin inclusion complexes by electrospray mass spectrometry

The results of previous works that have claimed to detect cyclodextrin inclusion complexes via the “soft” ionization technique of electrospray ionization mass spectrometry are revisited. A more extensive study of cyclodextrin mixtures with amino acids and small peptides demonstrates that amino acid and peptide “complexes” are detected by electrospray mass spectrometry regardless of the presence (or not) of an aromatic moiety on the side chain. Amino acids that may be least likely to form hydrophobic inclusion complexes with cyclodextrin in solution generally show the most intense complex ions. The data suggest that these “complexes” are, in all likelihood, electrostatic adducts formed during the electrospray process. Systematic controls are suggested to ensure that “false positives” do not negate many of the claims concerning the detection of solution-derived noncovalent compounds.