163 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
The feasibility of residential development in the newly master planned Ship Creek area of Anchorage, Alaska
No full textThesis (S.M.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 2004.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Includes bibliographical references (leaf 70).The aim of this thesis is to determine if a 40 unit condominium complex located in the Ship Creek area in Anchorage, Alaska, is financially feasible. Historically, Ship Creek has been an industrial area but recently the Alaska Railroad has master planned the area and hopes to entice developers to revitalize the area into a vibrant pedestrian friendly "village." Because Ship Creek is close to downtown, Ship Creek, Cook Inlet, and recreational trails, development in this area could be very desirable. A Market Analysis performed for this area determined that Anchorage's economy should continue with slow gradual growth. Also, it was forecasted that the demand for new condos in 2005 will be 340 units and that the supply of new condos will be 358. The proposed project will target the empty nester age group. Construction on the project is assumed to start in the third quarter of 2004 and end four quarters later in 2005. The benefit value of the development is calculated to be 95,087. A positive NPV means the project should be pursued. An IRR for the Net Cash Flows (all equity) was calculated to be 20% and the IRR for the equity contributor was calculated to be 59%. Although the "numbers" indicate that the project should be pursued, the numbers can not incorporate one important risk. Ship Creek is far from the vision created in the master plan. The proposed project risks being the first major redevelopment in the area. The proposed project is cautiously recommended. Due to Anchorage's dwindling supply of developable land, Ship Creek will eventually be redeveloped. Ship Creek's close proximity to downtown, combined with the belief that Anchorage has unmet demand for empty nester housing, makes the Ship Creek area attractive. However, because this development is one of the first major redevelopments in the area it is risky.by Shaun T. Debenham.S.M
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
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
An Efficient overloaded implementation of forward mode automatic differentiation in MATLAB
No full textThe Mad package described here facilitates the evaluation of first derivatives of multidimensional functions that are defined by computer codes written in MATLAB. The underlying algorithm is the well-known forward mode of automatic differentiation implemented via operator overloading on variables of the class fmad. The main distinguishing feature of this MATLAB implementation is the separation of the linear combination of derivative vectors into a separate derivative vector class derivvec. This allows for the straightforward performance optimization of the overall package. Additionally, by internally using a matrix (two-dimensional) representation of arbitrary dimension directional derivatives, we may utilize MATLAB's sparse matrix class to propagate sparse directional derivatives for MATLAB code which uses arbitrary dimension arrays. On several examples, the package is shown to be more efficient than Verma's ADMAT package [Verma 1998a].ACM Transactions on Mathematical Softwar
Hundreds of variants clustered in genomic loci and biological pathways affect human height
No full textMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways
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