A comparison of the gas phase acidities of phospholipid headgroups: Experimental and computational studies

Abstract

Proton-bound dimers consisting of two glycerophospholipids with different headgroups were prepared using negative ion electrospray ionization and dissociated in a triple quadrupole mass spectrometer. Analysis of the tandem mass spectra of the dimers using the kinetic method provides, for the first time, an order of acidity for the phospholipid classes in the gas phase of PE Ͻ PA Ͻ Ͻ PG Ͻ PS Ͻ PI. Hybrid density functional calculations on model phospholipids were used to predict the absolute deprotonation enthalpies of the phospholipid classes from isodesmic proton transfer reactions with phosphoric acid. The computational data largely support the experimental acidity trend, with the exception of the relative acidity ranking of the two most acidic phospholipid species. Possible causes of the discrepancy between experiment and theory are discussed and the experimental trend is recommended. The sequence of gas phase acidities for the phospholipid headgroups is found to (1) have little correlation with the relative ionization efficiencies of the phospholipid classes observed in the negative ion electrospray process, and (2)

Cellular Membrane Phospholipids Act as a Depository for Quaternary Amine Containing Drugs thus Competing with the Acetylcholine/Nicotinic Receptor

“…As a species becomes more acidic, it is more likely to form a strong electrostatic phospholipid – quaternary amine NCX amidst other competing species. Our observation that PI and PG are the most acidic phospholipids is consistent with negative mode mass spectrometric measurements made by Koivusalo et al 24 and Thomas et al 25 . The stability of such interactions was demonstrated by the work of Laskin et al and Woods et al When normalizing data, it is preferred to use a phospholipid-NCX to total phospholipid ratio but because PI, PG, PA, PE, and PS do not form protonated ions, the signal of PC was used as the normalization agent.…”

“…PC contains a fixed positive charge via the quaternary amine, whereas all of the other phospholipids preferentially ionize in negative ion mode. PG and PI tend to be the most acidic as reflected in mass spectrometric studies 24-25 . The negatively charged phosphate group in a phospholipid can form a strong and stable non-covalent complex (NCX) with the positively charged quaternary amine group 26-27 .…”

Switching radical stability by pH-induced orbital conversion

“…The kinetic method [43][44][45][46] was used for the determination of relative and absolute gas phase deprotonation enthalpies based on the relative ion abundances resulting from competitive dissociation of a mass-selected cluster ion. The application of this method to data from this instrument has previously been described 47 and further details of this analysis are provided in the Supplementary Information.…”

Gas‐phase dissociation of 1,4‐naphthoquinone derivative anions by electrospray ionization tandem mass spectrometry

“…[6] The versatility of this technique can be associated with the generation of protonated, [7,8] deprotonated, [9] metal complex, [10] and radical species [11] in the gas phase. These species can be further analyzed by tandem mass spectrometry.…”