The protonated nucleobases (C + H) + , (T + H) + , (U + H) + , (A + H) + , and (G + H) + are investigated in a combined experimental and computational study using differential mobility spectrometry (DMS), mass spectrometry, and electronic structure calculations. DMS is used to isolate individual tautomeric forms for each protonated nucleobase prior to characterization with HDX or CID. The population distributions of each protonated nucleobase formed by electrospray ionization (ESI) are dominated by a single tautomeric form, as is predicted by our calculations. However, all nucleobases present additional tautomers upon ESI, with these minor contributions to the ensemble populations attributed to additional higher energy metastable species. In addition to the tautomerderived species, additional ion signals in the DMS data are attributed to larger nucleobasecontaining clusters, which fragment post-DMS to yield bare ion and fragment ion signals that are consistent with those expected for the bare protonated nucleobases. Contributions from larger clustered species are instead distinguished by monitoring DMS ion signal as declustering potential voltages are ramped.

The fast and accurate determination of molecular properties is highly desirable for many facets of chemical research, particularly in drug discovery where pre-clinical assays play an important role in paring down large sets of drug candidates. Here, we present the use of supervised machine learning to treat differential mobility spectrometry – mass spectrometry data for ten topological classes of drug candidates. We demonstrate that the gas-phase clustering behavior probed in our experiments can be used to predict the candidates’ condensed phase molecular properties, such as cell permeability, solubility, polar surface area, and water/octanol distribution coefficient. All of these measurements are performed in minutes and require mere nanograms of each drug examined. Moreover, by tuning gas temperature within the differential mobility spectrometer, one can fine tune the extent of ion-solvent clustering to separate subtly different molecular geometries and to discriminate molecules of very similar physicochemical properties.

G-quadruplexes (G4s) have become important drug targets to regulate gene expression and telomere maintenance. Many studies on G4 ligand binding focus on determining the ligand binding affinities and selectivities. Ligands, however, can also affect the G4 conformation. Here we explain how to use electrospray ionization mass spectrometry (ESI-MS) to monitor simultaneously ligand binding and cation binding stoichiometries. The changes in potassium binding stoichiometry upon ligand binding hint at ligand-induced conformational changes involving a modification of the number of G-quartets. We investigated the interaction of three quadruplex ligands (PhenDC3, 360A and Pyridostatin) with a variety of G4s. Electrospray mass spectrometry makes it easy to detect K displacement (interpreted as quartet disruption) upon ligand binding, and to determine how many ligand molecules must be bound for the quartet opening to occur. The reasons for ligand-induced conversion to antiparallel structures with fewer quartets are discussed. Conversely, K intake (hence quartet formation) was detected upon ligand binding to G-rich sequences that did not form quadruplexes in 1mM K alone. This demonstrates the value of mass spectrometry for assessing not only ligand binding, but also ligand-induced rearrangements in the target sequence. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

Density functional theory (DFT) calculations and infrared multiple photon dissociation (IRMPD) spectroscopy are employed to probe [TM·(BH)] and [TM·(BH)] clusters [TM = Ag(I), Cu(I), Co(II), Ni(II), Zn(II), Cd(II)]. A comparison is made between the charge-transfer properties of the clusters containing the hydrogenated dodecaborate dianions, BH, and the fluorinated analogues, BF, for clusters containing Cd(II), Co(II), Ni(II), and Zn(II). IRMPD of the [TM·(BH)] and [TM·(BH)] species yields BH via hydride abstraction and BH in all cases. To further explore the IR-induced charge-transfer properties of the BX (X = H, F) cages, mixed-cage [TM(BH)(BF)] [TM = Co(II), Ni(II), Zn(II), Cd(II)] clusters were investigated. IRMPD of the mixed-cage species yielded appreciable amounts of BF and BH in most cases, indicating that charge-transfer to the central TM cation is a favorable process; formation of BF is the dominant process for the Co(II) and Ni(II) mixed-cage complexes. In contrast, the Zn(II) and Cd(II) mixed-cage complexes preferentially produced fragments of the form B HF , suggesting that H/F scrambling and/or fusion of the boron cages occurs along the IRMPD pathway.