The McMahon group investigates structures, energetics and reaction dynamics of gaseous ions. The majority of our work uses high pressure mass spectrometry (HPMS) to explore cluster ions. HPMS is uniquely suited for determining the energetics of gaseous ion-molecule equilibria, particularly those associated with ion-molecule clustering and exchange reactions. Using this technique we have amassed a considerable database for the energetics and kinetics of a wide variety of cluster species.
Over the past decade, we have also used the free electron laser at the Centre Laser Infrarouge d’Orsay (CLIO, Université Paris-Sud XI) to perform infrared multiple photon dissociation (IRMPD) spectroscopy experiments in the mid-infrared ‘fingerprint’ region. This is a form of consequence spectroscopy that allows detailed ion structures to be identified from characteristic absorption frequencies. These experiments are supported by high-performance quantum chemical calculations at Waterloo that help reveal the intrinsic properties of gas-phase ions. Current projects are listed below.
High Pressure Mass Spectrometry
Creating dianion-stabilized amino acid zwitterions
Isolated amino acids are non-zwitterionic, but can undergo charge separation when they are protonated, chelated with metals, or in the presence of solvent. They can also be produced through anion binding, and it was recently predicted that a glycine zwitterion can be stabilized by oxalate and malonate dianions. These complexes, however, appear to undergo rapid proton-transfer followed by dissociation, and have consequently not been experimentally identified.
We propose to produce stable zwitterion-dianion complexes by combining high pressure mass spectrometry with our recent success in identifying phenylalanine zwitterions stabilized by anion-π effects (see below). This will be accomplished using fluorine derivatives of phenylalanine; the increased π-acidity of the ring will enable stronger anion-binding, and therefore strengthen the dianion complex with phenylalanine with respect to proton transfer. We are currently using density functional theory and ab initio calculations to predict the conditions necessary to create these ions experimentally. In the near future, HPMS will be used to reveal practical insight into their stability by determining thermochemical data.
Infrared Spectroscopy of Biological Ions
Exploring anionic interactions in the gas phase
The dominant isomers of biomolecules are typically explained by the number of non-covalent interactions that stabilize their structures. Hydrogen bonds, for example, are responsible for DNA base pairing while π-π stacking and cation-π interactions are often observed in proteins. Perhaps counterintuitively, it is also possible to stabilize molecules through anion-π interactions; either by an interaction between the anion and positively-charged edge of the aromatic ring, or by adding electron withdrawing groups to the ring in order to promote face-directed interactions. Because of their odd nature, little is known about anion-π activity other than that the stabilizing effect, 20–70 kJ/mol, is similar to cation-π or hydrogen bonds, and that they typically occur in proteins near the latter. This information, however, comes from condensed phase work and raises the question as to whether anion-π interactions are truly significant, or if they are simply an artefact of the interplay between hydrogen bonding and solvent effects.
To understand these interactions, we developed four experiments. The first identifies the structures of anion-bound fluorinated phenylalanine derivatives using IRMPD spectroscopy and computational chemistry, while the second uses high-performance calculations to systematically vary the degree of fluorine substitution on anion-bound phenylalanine and Phe-Phe dipeptides in order to determine the extent of influence anion-π interactions exert on structures.
The third project explores the effect of singly solvating chloride-bound phenylalanine and pentafluorophenylalanine; by sequentially adding water molecules to build solvation shells around these complexes, it will be possible to assess the influence of solvent effects, and to gauge whether or not hydrogen bonding between water and phenylalanine enforces a geometry with an anion-π interaction. The fourth series of experiments deals with anion-bound homo- and heterogeneous dimers of phenylalanine (both fluorinated and non-fluorinated), aspartic acid, and glutamic acid. The goal of this project is to compare gas-phase and crystal structures to determine the intrinsic properties of the anion-π interaction. Each of these experiments combine IRMPD spectroscopy and computational modeling with Gaussian to determine the gas-phase structures.
Characterizing the proton-bound glutathione dimer
Glutathione is a tripeptide composed of glycine, cysteine, and glutamine. It plays an important role in protecting cells from oxidation by free radicals, and is also involved in protein and DNA syntheses, transport through cell membranes, enzyme activity, and metabolic processes. The biological importance of glutathione necessitates a thorough understanding of its structure. For this reason, we have combined IRMPD spectroscopy, hydrogen-deuterium exchange kinetic experiments, and computational chemistry to identify the gas-phase structure (or structures) of protonated glutathione and its proton-bound dimer. This will reveal the intrinsic properties of glutathione and, by comparing with solution phase data, will establish the influence of solvent on its behaviour.
Identifying the structure of Cu2+-angiotensin II
Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) is an “S”-shaped hormone that increases blood pressure by constricting blood vessels. This activity can be counteracted by copper chelation, which, due to the peptide’s shape, is expected to occur at one of two binding pockets (Asp-Arg-Val-Tyr or Ile-His-Pro-Phe). We aim to resolve the structure of Cu2+-bound angiotensin II using IRMPD spectroscopy in conjunction with computational chemistry. This will help reveal angiotensin’s physiological behaviour and, because this hormone is large, will develop basin hopping as a reliable method for examining the potential energy landscapes of complex molecules.
Predicting Ion Behaviour Computationally
Solvent-dependent deprotonation of p-hydroxybenzoic acid
P-hydroxybenzoic acid is a metabolite that deprotonates to form an alkoxide in the gas-phase, but a carboxylate in aqueous solution. The physical behaviour of this molecule is therefore modified by solvent effects, and we aim to reveal the underlying chemistry of this process using computational chemistry (Zach Johnston, Michael Burt, and Scott Hopkins). This project uses an energy basin-hopping algorithm to generate candidate structures for geometry optimization by density functional theory (DFT). This program automatically varies an ion’s bond and torsional angles until an energy minimum is identified using AMBER force fields, allowing large molecules to be thoroughly analysed through multiple iterations. This is particularly useful for examining the sequential solvation of gas-phase ions since likely binding sites can be determined by moving the added molecules about the surface of the ion. In this way, structures of p-hydroxybenzoic acid solvated by up to ten water molecules will be determined to identify the influence of solvent on the deprotonation process.
- VG Instruments MM 8-80 magnetic mass spectrometer with high-pressure source.
- VG Instruments 70-70 double focusing analytical mass spectrometer with high-pressure source.