Combining density functional theory (DFT) and collision cross-section (CCS) calculations to analyze the gas-phase behaviour of small molecules and their protonation site isomers

Electrospray ion mobility-mass spectrometry (IM-MS) data show that for some small molecules, two (or even more) ions with identical sum formula and mass, but distinct drift times are observed. In spite of showing their own unique and characteristic fragmentation spectra in MS/MS, no configurational or constitutional isomers are found to be present in solution. Instead the observation and separation of such ions appears to be inherent to their gas-phase behaviour during ion mobility experiments. The origin of multiple drift times is thought to be the result of protonation site isomers ('protomers'). Although some important properties of protomers have been highlighted by other studies, correlating the experimental collision cross-sections (CCSs) with calculated values has proven to be a major difficulty. As a model, this study uses the pharmaceutical compound melphalan and a number of related molecules with alternative (gas-phase) protonation sites. Our study combines density functional theory (DFT) calculations with modified MobCal methods (e.g. nitrogen-based Trajectory Method algorithm) for the calculation of theoretical CCS values. Calculated structures can be linked to experimentally observed signals, and a strong correlation is found between the difference of the calculated dipole moments of the protomer pairs and their experimental CCS separation

Smart Grid in a New Zealand Context

The following report examines the Smart Grid in the context of New Zealand. It begins by developing a definition for what the Smart Grid actually by looking at various international organisations views. Defining the Smart Grid as a modernisation of the existing system to improve efficiency and reliability and that it will be a gradual process of time that has already begun. The report then goes on to look at Smart Grid progress around the world. It examines work in North America, Europe, Asia and Australia. By examining the government policies around Smart Grids and the various pilot projects that have been implemented globally, a better understanding the progress New Zealand has made can be achieved. A major point that has been noted in this work is the shear size of the investment and resources that have already used in the Smart Grid arena. The next section of the report looks at international standards development. The focus is on work carried out by the International Electrotechnical Commission the National Institute of Standards and Technology in North America. Both these organisations have developed a Smart Grid standards roadmap outlining a number of current standards applicable to Smart Grids, identifying the gaps in the standards portfolio and developing plans to address those shortcomings. The report then goes on to examine current Smart Grid progress in the New Zealand context. The various different sectors in the New Zealand electricity industry are examined individually including government, generation, transmission, distribution and retail. The findings show there is already good progress in Smart Grid related goals such as renewable energy generation and peak load management. However, there is still some work needed for aspects such as AMI standardisation. The report then finishes with a discussion and concluding remarks

Very Low Frequency Observations During an Active DC Injection Campaign that Simulated Geomagnetic Storm effects on High Voltage Transformers

In January 2023, in collaboration with our industry partner Transpower Ltd (New Zealand’s national grid operator), a campaign was undertaken to inject large currents into operating high voltage transformers. New Zealand’s high voltage DC (HVDC) link was used to inject current directly into the ground at Haywards substation near Wellington, including into several 216MVA 220 kV / 110 kV autotransformers. Six injection test periods occurred, each lasting 1-2 hours. The peak current injected into the ground was about 621 A, spread across several transformers within the Haywards substation. The injection campaign was undertaken for New Zealand’s Endeavour programme “Solar Tsunamis: Space-Weather Prediction and Risk Mitigation for New Zealand’s Energy Infrastructure”. The technique of substation monitoring using nearby very low frequency (VLF) receivers has been previously reported by the lead author, based on observations of the Halfway Bush substation (HWB) in Dunedin, New Zealand. Evidence of harmonic distortion through enhanced odd and even 50 Hz harmonic amplitudes during geomagnetically induced current (GIC) events of up to 50 A, associated with large geomagnetic storms in 2017 and 2018, have already been observed and analysed in detail. Typically, enhancements in the amplitude of harmonics in the 100 Hz to 600 Hz range have been detected during GIC events. The VLF observations from HWB are consistent with the idea that the local transformers radiate even harmonics of the 50 Hz fundamental mains frequency due to half-cycle saturation driven by additive dc flux induced by GIC. During the Active Injection campaign at Haywards Station, two identical VLF receiving systems were deployed around the substation. Each VLF system comprised a set of orthogonal magnetic field loop aerials. Preliminary results from the VLF harmonic data suggest that observed variations in amplitude in the 100 – 600 Hz frequency range were correlated with temporal variations in the injected ground current, particularly after the current had been applied for more than 20 minutes. Prior to that, a slow increase in harmonic distortion occurred, beginning at the time of the injection onset. For injected substation earth currents ranging from 300 A – 600 A (about 20 A – 35 A for individual autotransformers) even small variations of the order of 10’s of amps appeared to be well correlated with the VLF amplitude variations of even order harmonics. In this study we present the VLF data during the injection events, describing the responses observed from a large, complex substation experiencing geomagnetic storm-like effects

An Overview of the Unique DC Injection Campaign for Replicating GICs on High Voltage Transformers in New Zealand

Introduction: Between 21 and 29 January 2023, with the assistance of Transpower, we successfully utilised New Zealand's HVDC link to directly introduce current into the ground at Haywards substation. Our objective was to simulate the efffects of geomagnetically induced currents (GICs) and observe their impact on two 216 MVA, 220/110 kV autotransformers and one 80 MVA transformer, as well as to monitor the associated transmission lines

Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates

Glutathione-S-transferases are key to the cellular detoxification of xenobiotics and products of oxidative damage. GSTs catalyse the reaction of glutathione (GSH) with electrophiles to form stable thioether adducts. GSTK1-1 is the main GST isoform in the mitochondrial matrix, but the GSTA1-1 and GSTA4-4 isoforms are also thought to be in the mitochondria with their distribution altering in transformed cells, thus potentially providing a cancer specific target. A mitochondria-targeted version of the GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), MitoCDNB, has been used to manipulate the mitochondrial GSH pool. To finesse this approach to target particular GST isoforms in the context of cancer, here we have determined the kcat/Km for the human isoforms of GSTK1-1, GSTA1-1 and GSTA4-4 with respect to GSH and CDNB. We show how the rate of the GST-catalysed reaction between GSH and CDNB analogues can be modified by both the electron withdrawing substituents, and by the position of the mitochondria-targeting triphenylphosphonium on the chlorobenzene ring to tune the activity of mitochondria-targeted substrates. These findings can now be exploited to selectively disrupt the mitochondrial GSH pools of cancer cells expressing particular GST isoforms

Protomers of Benzocaine: Solvent and Permittivity Dependence

The immediate environment of a molecule can have a profound influence on its properties. Benzocaine, the ethyl ester of para-aminobenzoic acid, which finds an application as a local anesthetic (LA), is found to adopt in its protonated form at least two populations of distinct structures in the gas phase and their relative intensities strongly depend on the properties of the solvent used in the electrospray ionization (ESI) process. Here we combine IR-vibrational spectroscopy with ion mobility-mass spectrometry (IM-MS) to yield gas-phase IR spectra of simultaneously m/z and drift-time resolved species of benzocaine. The results allow for an unambiguous identification of two protomeric species - the N- and O-protonated form. Density functional theory (DFT) calculations link these structures to the most stable solution and gas-phase structures, respectively, with the electric properties of the surrounding medium being the main determinant for the preferred protonation site. The fact that the N-protonated form of benzocaine can be found in the gas phase is owed to kinetic trapping of the solution phase structure during transfer into the experimental setup. These observations confirm earlier studies on similar molecules where N- and O-protonation has been suggested

Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β-subunit

Heterodimeric hCG is one of the key hormones determining early pregnancy success. We have previously identified rare missense mutations in hCGβ genes with potential pathophysiological importance. The present study assessed the impact of these mutations on the structure and function of hCG by applying a combination of in silico (sequence and structure analysis, molecular dynamics) and in vitro (co-immunoprecipitation, immuno- and bioassays) approaches. The carrier status of each mutation was determined for 1086 North-Europeans [655 patients with recurrent miscarriage (RM)/431 healthy controls from Estonia, Finland and Denmark] using PCR-restriction fragment length polymorphism. The mutation CGB5 p.Val56Leu (rs72556325) was identified in a single heterozygous RM patient and caused a structural hindrance in the formation of the hCGα/β dimer. Although the amount of the mutant hCGβ assembled into secreted intact hCG was only 10% compared with the wild-type, a stronger signaling response was triggered upon binding to its receptor, thus compensating the effect of poor dimerization. The mutation CGB8 p.Pro73Arg (rs72556345) was found in five heterozygotes (three RM cases and two control individuals) and was inherited by two of seven studied live born children. The mutation caused ∼50% of secreted β-subunits to acquire an alternative conformation, but did not affect its biological activity. For the CGB8 p.Arg8Trp (rs72556341) substitution, the applied in vitro methods revealed no alterations in the assembly of intact hCG as also supported by an in silico analysis. In summary, the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCGβ genes CGB5 and CGB8