7 July 2017

The American Chemical Society (ACS) has just published the best 2016 papers by Australian authors and the School of Chemistry was included in this list. Congratulations to the following people:-

Physical chemistry

Benchmarking Calculations of Excitonic Couplings between Bacteriochlorophylls
Dr Ivan Kassal

Dr Ivan Kassal

Elise P. Kenny and Ivan Kassal*. J. Phys. Chem. B,, 120 (1), pp 25–32, 2016. DOI: 10.1021/acs.jpcb.5b08817

Excitonic couplings between (bacterio)chlorophyll molecules are necessary for simulating energy transport in photosynthetic complexes. Many techniques for calculating the couplings are in use, from the simple (but inaccurate) point-dipole approximation to fully quantum-chemical methods. We compared several approximations to determine their range of applicability, noting that the propagation of experimental uncertainties poses a fundamental limit on the achievable accuracy. In particular, the uncertainty in crystallographic coordinates yields an uncertainty of about 20% in the calculated couplings. Because quantum-chemical corrections are smaller than 20% in most biologically relevant cases, their considerable computational cost is rarely justified. We therefore recommend the electrostatic TrEsp method across the entire range of molecular separations and orientations because its cost is minimal and it generally agrees with quantum-chemical calculations to better than the geometric uncertainty. Understanding these uncertainties can guard against striving for unrealistic precision; at the same time, detailed benchmarks can allow important qualitative questions-which do not depend on the precise values of the simulation parameters-to be addressed with greater confidence about the conclusions.

Geometry, Supertransfer, and Optimality in the Light Harvesting of Purple Bacteria

Sima Baghbanzadeh and Ivan Kassal*. J. Phys. Chem. Lett.,, 7 (19), pp 3804–3811, 2017. DOI: 10.1021/acs.jpclett.6b01779

The remarkable rotational symmetry of the photosynthetic antenna complexes of purple bacteria has long been thought to enhance their light harvesting and excitation energy transport. We study the role of symmetry by modeling hypothetical antennas whose symmetry is broken by altering the orientations of the bacteriochlorophyll pigments. We find that in both LH2 and LH1 complexes, symmetry increases energy transfer rates by enabling the cooperative, coherent process of supertransfer. The enhancement is particularly pronounced in the LH1 complex, whose natural geometry outperforms the average randomized geometry by 5.5 standard deviations, the most significant coherence-related enhancement found in a photosynthetic complex.

Molecular Resolution in situ Imaging of Spontaneous Graphene Exfoliation
Professor Greg Warr

Prof Greg Warr

Gregory G. Warr et al. J. Phys. Chem. Lett.,, 7 (16), pp 3118–3122, 2016. DOI: 10.1021/acs.jpclett.6b01323

All reported methods of graphene exfoliation require external energy input, most commonly from sonication,1 shaking,2 or stirring.3 The reverse process-aggregation of single or few layer graphene sheets-occurs spontaneously in most solvents. This makes producing, and especially storing, graphene in economic quantities challenging,4,5 which is a significant barrier to widespread commercialization. This study reveals ionic liquids (ILs) can spontaneously exfoliate graphene from graphite at room temperature. The process is thermally activated and follows an Arrhenius-type behavior, resulting in thermodynamically stable IL/graphene suspensions. Using atomic force microscopy, the kinetics of the exfoliation could be followed in situ and with subnanometer resolution, showing that both the size and the charge of the constituent IL ions play a key role. Our results provide a general molecular mechanism underpinning spontaneous graphene exfoliation at room temperature in electrically conducting ILs, paving the way for their adoption in graphene-based technology.

Polymer science

Shape-Dependent Activation of Cytokine Secretion by Polymer Capsules in Human Monocyte-Derived Macrophages
Dr Markus Muellner

Dr Markus Muellner

Markus Müllner et al. Biomacromolecules, 17 (3), pp 1205–1212, 2017. DOI: 10.1021/acs.biomac.6b00027

Particles with tailored geometries have received significant attention due to their specific interactions with biological systems. In this work, we examine the effect of polymer capsule shape on cytokine secretion by human monocyte-derived macrophages. Thiolated poly(methacrylic acid) (PMASH) polymer capsules with different shapes (spherical, short rod-shaped, and long rod-shaped) were prepared by layer-by-layer assembly. The effect of PMASH capsule shape on cellular uptake and cytokine secretion by macrophages differentiated from THP-1 monocytes (dTHP-1) was investigated. PMASH capsules with different shapes were internalized to a similar extent in dTHP-1 cells. However, cytokine secretion was influenced by capsule geometry: short rod-shaped PMASH capsules promoted a stronger increase in TNF-α and IL-8 secretion compared with spherical (1.7-fold in TNF-α and 2.1-fold in IL-8) and long rod-shaped (2.8-fold in TNF-α and 2.0-fold in IL-8) PMASH capsules in dTHP-1 cells (capsule-to-cell ratio of 100:1). Our results indicate that the immunological response based on the release of cytokines is influenced by the shape of the polymer capsules, which could be potentially exploited in the rational design of particle carriers for vaccine delivery.

Biological and medicinal chemistry

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles
Associate Professor Mat Todd

A/Prof Mat Todd

Alice E. Williamson, Paul M. Ylioja, Murray N. Robertson, Matin Dean, Zoe Hungerford, Matthew J. Tarnowski, Peter Turner, Laura White and Matthew H. Todd* et al. ACS Cent. Sci., 2 (10), pp 687–701, 2016. DOI: 10.1021/acscentsci.6b00086

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues
Professor Michael Kassiou

Prof Michael Kassiou

Samuel D. Banister, Mitchell Longworth and Michael Kassiou* et al. ACS Chem. Neurosci.,, 7 (9), pp 1241–1254, 2017. DOI: 10.1021/acschemneuro.6b00137

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.45–36 nM) and CB2 (EC50 = 4.6–128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1 activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1–1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 °C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB1, but not CB2, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB1-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Δ9-THC and earlier generations of SCs.

Organic chemistry

The Formation of Seven-Membered Heterocycles under Mild Pictet–Spengler Conditions: A Route to Pyrazolo[3,4]benzodiazepines
Professor Michael Kassiou

Prof Michael Kassiou

Timothy A. Katte, Tristan A. Reekie, William T. Jorgensen, and Michael Kassiou*. J. Org. Chem.,, 81 (11), pp 4883–4889, 2016. DOI: 10.1021/acs.joc.6b00710

Reported is a method for the synthesis of seven-membered heterocycles via a Pictet–Spengler condensation reaction under very mild conditions. High substrate scope allows for use of aldehydes using catalytic amounts of acetic acid yielding 39-90% and ketones using catalytic amounts of trifluoroacetic acid yielding 25-83%.

Theoretical and computational chemistry

Frequency Scale Factors for Some Double-Hybrid Density Functional Theory Procedures: Accurate Thermochemical Components for High-Level Composite Protocols
Emeritus Professor Leo Radom

E/Prof Leo Radom

Bun Chan* and Leo Radom*. J. Chem. Theory Comput.,, 12 (8), pp 3774–3780, 2016. DOI: 10.1021/acs.jctc.6b00554

In the present study, we have obtained geometries and frequency scale factors for a number of double-hybrid density functional theory (DH-DFT) procedures. We have evaluated their performance for obtaining thermochemical quantities [zero-point vibrational energies (ZPVE) and thermal corrections for 298 K enthalpies (deltaH298) and 298 K entropies (S298)] to be used within high-level composite protocols (using the W2X procedure as a probe). We find that, in comparison with the previously prescribed protocol for optimization and frequency calculations (B3-LYP/cc-pVTZ+d), the use of contemporary DH-DFT methods such as DuT-D3 and DSD-type procedures leads to a slight overall improved performance compared with B3-LYP. A major strength of this approach, however, lies in the better robustness of the DH-DFT methods in that the largest deviations are notably smaller than those for B3-LYP. In general, the specific choices of the DH-DFT procedure and the associated basis set do not drastically change the performance. Nonetheless, we find that the DSD-PBE-P86/aug'-cc-pVTZ+d combination has a very slight edge over the others that we have examined, and we recommend its general use for geometry optimization and vibrational frequency calculations, in particular within high-level composite methods such as the higher-level members of the WnX series of protocols. The scale factors determined for DSD-PBE-P86/aug'-cc-pVTZ+d are 0.9830 (ZPVE), 0.9876 (deltaH298), and 0.9923 (S298).

Restricted-Open-Shell G4(MP2)-Type Procedures

Leo Radom* et al. J. Phys. Chem. A,, 120 (46), pp 9299–9304, 2016. DOI: 10.1021/acs.jpca.6b09361

In the present study, we have reformulated the G4(MP2) and G4(MP2)-6X procedures for use with a restricted-open-shell (RO) formalism. We find that the resulting ROG4(MP2) and ROG4(MP2)-6X procedures generally perform comparably to the original unrestricted (U) variants, including their performance on radicals. Our analysis suggests that this is due mainly to the inclusion of empirical parameters that overcome the slightly less good performance of the U variants. However, a major practical advantage of ROG4(MP2) and ROG4(MP2)-6X is that they can be used in a wider range of computational chemistry software packages than the U analogs. We have demonstrated the importance of this aspect with a large-scale ROG4(MP2)-6X computation for the dissociation of the dodecahedryl dimer (C20H19)2.