128 research outputs found
Computational evidence for structural consequences of kiteplatin damage on DNA
No full textThe reaction of the potential anticancer drug
kiteplatin, cis-[PtCl2(cis-1,4-DACH)], with oligomers of
single- and double-stranded DNA ranging from 2 to 12
base pairs in length was performed as a model for DNA
interaction. The potential for conformational flexibility of
single-stranded adducts was examined with density functional
theory (DFT) and compared with data from 1H-NMR
1D and 2D spectroscopy. This indicates the presence of
multiple conformations of an adduct with d(GpG), but only
one form of the adduct with d(TGGT). The importance of
a suitable theoretical model, and in particular basis set, in
reproducing experimental data is demonstrated. The DFT
theoretical model was extended to platinated base pair step
(GG/CC), allowing a comparison to the related compounds
cisplatin and oxaliplatin. Adducts of kiteplatin with larger
fragments of double-stranded DNA, including tetramer,
octamer, and dodecamer, were studied theoretically using
hybrid quantum mechanics/molecular mechanics methods.
Structural parameters of all the base-paired models were
evaluated and binding energies calculated in gas phase and in solution; these are compared across the series and
also with the related complexes cisplatin and oxaliplatin,
thus revealing insights into how kiteplatin binds to DNA
and similarities and differences between this and related
compounds
Density Functional Theory Studies of Interactions of Ruthenium–Arene Complexes with Base Pair Steps
No full textModulation of stacking interactions by transition-metal coordination: ab initio benchmark studies
No full textA series of ab initio calculations are used to determine the CHπ and ππ-stacking interactions of aromatic rings coordinated to transition-metal centres. Two model complexes have been employed, namely, ferrocene and chromium benzene tricarbonyl. Benchmark data obtained from extrapolation of MP2 energies to the basis set limit, coupled with CCSD(T) correction, indicate that coordinated aromatic rings are slightly weaker hydrogen-bond acceptors but are significantly stronger hydrogen-bond donors than uncomplexed rings. It is found that ππ stacking to a second benzene is stronger than in the free benzene dimer, especially in the chromium case. This is assigned, by use of energy partitioning in the local correlation method, to dispersion interactions between metal d and benzene π orbitals. The benchmark data is also used to test the performance of more efficient theoretical methods, indicating that spin-component scaling of MP2 energies performs well in all cases, whereas various density functionals describe some complexes well, but others with errors of more than 1 kcal mol−1
Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides
No full textLigand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-β1–16 peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 Å and 5°. Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-β1–16 peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 Å over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand
Piloting the PREVIEW-ED Tool in Fraser Health Authority
No full textIn 2016, Fraser Health (FH) partnered with the Langara School of Nursing and senior nurse consultant, Marilyn El Bestawiand to pilot the PREVIEW-ED© tool.
Two (2) term 8 Bachelor of Science in Nursing (BSN) students facilitated implementation of the tool with Fraser Health’s first cohort of 176 residents across 4 Fraser Health Care Homes.
Students worked with Care Aides who completed the PREVIEW-ED© tool to prevent transfers to the Emergency Department for: pneumonia, congestive heart failure, urinary tract infections and dehydration.
A noted 71% reduction in Emergency Departments (ED) transfers for tool sensitive conditions.
This is now a best practice for Fraser Health Residential Care Homes
Density Functional Theory Studies of Interactions of Ruthenium–Arene Complexes with Base Pair Steps
No full textDensity functional theory (DFT) calculations have been performed to determine the strength and geometry of intermolecular interactions of “piano-stool” ruthenium arene complexes, which show potential as anticancer treatments. Model complexes with methane and benzene indicate that the coordinated arene has C–H···π acceptor ability similar to that of free benzene, whereas this arene acts as a much stronger C–H donor or partner in π-stacking than free benzene. The source of these enhanced interactions is identified as a combination of electrostatic and dispersion effects. Complexes of Ru-arene complexes with base-pair step fragments of DNA, in which the arene has the potential to act as an intercalator, have also been investigated. Binding energies are found to be sensitive to the size and nature of the arene, with larger and more flexible arenes having stronger binding. π-stacking and C–H···π interactions between arene and DNA bases and hydrogen bonds from coordinated N–H to DNA oxygen atoms, as well as covalent Ru–N bonding, contribute to the overall binding. The effect of complexation on DNA structure is also examined, with larger rise and more negative slide values than canonical B-DNA observed in all cases
DNA fragment conformations in adducts with Kiteplatin
No full textThe anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed, carrier ligands such as 2,2′-bipiperidine, which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds, were introduced ("retro-modelling" approach). In the present study we investigate the effect of cis-1,4-diaminocyclohexane (cis-1,4-DACH) on the formation, stability, and stereochemistry of (cis-1,4-DACH)Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3′- and/or 5′-substituents). Interesting features of this ligand, absent in previous retro-modelling studies, include the large bite angle (expected to impede the ease of interconversion between possible conformers), the presence of two protons on each nitrogen (a characteristic associated with antitumor activity), and the absence of chiral centres. The use of cis-1,4-DACH has made it possible to detect different conformers in a system containing a primary diamine carrier ligand associated with anticancer activity and to confirm the previous hypothesis that the coexistence of different conformers established in studies of retro models having relatively bulky ligands is not an artefact resulting from carrier-ligand bulk. Moreover, the data for the (cis-1,4-DACH)Pt(d(GpG)) and (cis-1,4-DACH)Pt(d(GGTTT)) adducts indicate that at a temperature close to the physiological one (40 °C) HH1 and ΔHT1 conformers are present in comparable amounts. In contrast, at low temperature (close to 0 °C) the equilibrium shifts dramatically toward the more stable HH1 conformer (for the (cis-1,4-DACH)Pt(d(TGGT)) adduct the HH1 conformer is always dominant, even at high temperature). Notably, (cis-1,4-DACH)PtCl2 (Kiteplatin) has been recently reinvestigated and found to be particularly active against colorectal cancer (including oxaliplatin-resistant phenotypes)
The shaping of student knowledge: learning with dynamic geometry software
No full textThe focus of this paper is a software genre usually referred to as ‘dynamic geometry’ because of the ability of the user to dynamically manipulate geometrical figures created with the software tool. Using data from a longitudinal study of 12-13 students’ use of dynamic geometry software, the focus of the analysis is on the interpretations the students make of geometrical objects and relationships when using this form of software. The analysis suggests that the students’ mathematical reasoning is shaped by their interactions with the software in that their ability to explain geometrical facts and relationships evolves from imprecise, ‘everyday’ expressions, through reasoning that is overtly mediated by the software environment, to mathematical explanations of the geometric situation that transcend the particular tool being used. Such findings suggest that curriculum initiatives that encourage the use of dynamic geometry software are appropriate but that the incorporation of such software into classroom practices is unlikely to be straightforward
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