How useful is molecular modelling in combination with ion mobility mass spectrometry for ‘small molecule’ ion mobility collision cross-sections?

Abstract

Ion mobility mass spectrometry is used to measure the drift-time of an ion. The drift-time of an ion can be used to calculate the collision cross-section (CCS) in travelling wave ion mobility (e.g. Waters Synapt and Vion instruments) or directly determine the experimental CCS (e.g. Agilent 6560 instrument and many drift-tube instruments). A comparison of the experimental CCS and theoretical CCS values obtained from trajectory method He(g) parameterised MOBCAL and N2(g) parameterised MOBCAL software, for a range of 20 'small molecules' is presented. This study utilises density functional theory B3LYP methods and the 6-31G+(d,p) basis set to calculate theoretical CCS values. This study seeks to assess the accuracy of a common procedure using CCS calibration with poly-(d/l)-alanine derived from drift-cell measurements and the original release of MOBCAL software and compare it with recent improvements with a drug-like molecule calibration set and a revision of MOBCAL parameterised for N2(g) drift gas. This study represents one of the first quantitative evaluations of the agreement between theoretical CCS and experimental CCS values for a range of small pharmaceutically relevant molecules using travelling wave ion mobility mass spectrometry. Accurate theoretical CCS may allow optimisation of ion mobility separations in silico, provide CCS databases that can confirm structures without the need for alternative analytical tools such as nuclear magnetic resonance spectroscopy (NMR) and assignment of unknowns and positional isomers without requiring reference materials.

Collision cross section prediction of deprotonated phenolics in a travelling-wave ion mobility spectrometer using molecular descriptors and chemometrics

“…7). The slope of the fit was~1.12, which is close to the reported expected slope (~1.15) obtained for molecules having a small number of rotatable bonds [24]. The average number of rotatable bonds for the entire dataset is 3.5 (median ¼ 4).…”

“…The average number of rotatable bonds for the entire dataset is 3.5 (median ¼ 4). It has been previously hypothesized that mobcal (N 2 ) is sub-optimal and overestimates the calculated CCS for compounds with limited conformational flexibility [24], such as phenolics. To account for this bias, the predicted CCS values were corrected using the linear regression slope, referred as corrected modified mobcal (N 2 ).…”

“…Structures were optimized/minimized using the Smart Minimizer algorithm, which is a combination of steepest descent and conjugate descent algorithms, in DS using 2000 minimizing steps with a 0.1 minimizing RMS gradient using the CHARMM forcefield. Owing to the low number of rotatable bonds and the relatively rigid structure of the test molecules, they are expected to have a relatively small distribution of conformational complexity and thus the global minimum is most likely achievable [24]. A negative charge (À1) was placed by removing a hydrogen from the all titratable regions of the structure followed by structure re-minimization.…”

A Careful Consideration of the Influence of Structure, Partial charges and Basis Sets on Collision Cross Sections of Monosaccharides when Comparing Values from DFT Calculated Conformers to those Obtained Experimentally

“…For instance, Warnke et al 14 demonstrated that combining IM-MS and infrared multiple photon dissociation (IRMPD) spectroscopy reveals two distinct protomers of benzocaine, where depending on the protonation site (N or O), a unique N-H and O-H stretch frequencies appear. Similarly, Voronina et al 28 utilised IM-MS and cold-ion spectroscopy to study the bradykinin fragment (BK [1][2][3][4][5] 2+ ) ions elucidating cis-trans and trans-cis conformations for the more compact conformer and kinetically trapped trans-trans configuration for the larger conformer, highlighting the cis-trans isomerization of the peptide bonds during the desolvation process. In both cases, IM-MS data was supplemented with gas-phase IR experiments which in turn were supported by high-level calculations to assign potential in vacuo species.…”

“…2 Both IM-MS techniques have been applied to a broad scope of species to elucidate structural information, including small drug-like molecules, 3,4 carbohydrates, 5,6 DNA and RNA, 7 proteins 8,9 and protein complexes. 9 It has also used to study protein unfolding, 8 refolding, 9,10 proton and electron transfer mechanisms 11,12 and solvent adduct effects on the protein structure.…”