Can density functional theory (DFT) be used as an aid to a deeper understanding of tandem mass spectrometric fragmentation pathways?

Prediction of tandem mass spectrometric (MS/MS) fragmentation for non-peptidic molecules based on structure is of immense interest to the mass spectrometrist. If a reliable approach to MS/MS prediction could be achieved its impact within the pharmaceutical industry could be immense. Many publications have stressed that the fragmentation of a molecular ion or protonated molecule is a complex process that depends on many parameters, making prediction difficult. Commercial prediction software relies on a collection of general heuristic rules of fragmentation, which involve cleaving every bond in the structure to produce a list of 'expected' masses which can be compared with the experimental data. These approaches do not take into account the thermodynamic or molecular orbital effects that impact on the molecule at the point of protonation which could influence the potential sites of bond cleavage based on the structural motif. A series of compounds have been studied by examining the experimentally derived high-resolution MS/MS data and comparing it with the in silico modelling of the neutral and protonated structures. The effect that protonation at specific sites can have on the bond lengths has also been determined. We have calculated the thermodynamically most stable protonated species and have observed how that information can help predict the cleavage site for that ion. The data have shown that this use of in silico techniques could be a possible way to predict MS/MS spectra. Copyright (C) 2009 John Wiley & Sons, Ltd.

Surface physics at the nano-scale via scanning probe microscopy and molecular dynamics simulations

Probe-based scanning microscopes, such as the STM and the AFM, are used to obtain the topographical and electronic structure maps of material surfaces, and to modify their morphologies on nanoscopic scales. They have generated new areas of research in condensed matter physics and materials science. We will review some examples from the fields of experimental nano-mechanics, nano-electronics and nano-magnetism. These now form the basis of the emerging field of Nano-technology. A parallel development has been brought about in the field of Computational Nano-science, using quantum-mechanical techniques and computer-based numerical modelling, such as the Molecular Dynamics (MD) simulation method. We will report on the simulation of nucleation and growth of nano-phase films on supporting substrates. Furthermore, a theoretical modelling of the formation of STM images of metallic clusters on metallic substrates will also be discussed within the non-equilibrium Keldysh Green function method to study the effects of coherent tunnelling through different atomic orbitals in a tip-sample geometry.

Effects of reflow process on the reliability of flip chip on flex interconnections using anisotropic conductive adhesives

In this paper, the effects of the solder reflow process on the reliability of anisotropic conductive film (ACF) interconnections for flip chip on flex (FCOF) applications are investigated. Experiments as well as computer modeling methods have been used. In the experiments, it was found that the contact resistance of ACF joints increased after the subsequent reflow process, and the magnitude of this increase was strongly correlated to the peak temperature of the reflow profile. Nearly 40% of the joints were opened (i.e. lifted away from the pad) after the reflow process with 260 °C peak temperature while no opening was observed when the peak temperature was 210 °C. It is believed that the CTE mismatch between the polymer particle and the adhesive matrix is the main cause of this contact degradation. It was also found that the ACF joints after the reflow process with 210 °C peak temperature showed a high ability to resist water absorption under steady state 85 °C/85%RH conditions, probably because the curing degree of the ACF was improved during the reflow process. To give a good understanding, a 3D model of an ACF joint structure was built and finite element analysis was used to predict the stress distribution in the conductive particles, adhesive matrix and metal pads during the reflow process.

Effects of solder reflow on the reliability of flip-chip on flex interconnections using anisotropic conductive adhesives

This work describes the work of an investigation of the effects of solder reflow process on the reliability of anisotropic conductive film (ACF) interconnection for flip-chip on flex (FCOF) applications. Experiments as well as computer modeling methods have been used. The results show that the contact resistance of ACF interconnections increases after the reflow and the magnitude of the increase is strongly correlated to the peak reflow temperature. In fact, nearly 40 percent of the joints are open when the peak reflow temperature is 260°C, while there is no opening when the peak temperature is 210°C. It is believed that the coefficient of thermal expansion (CTE) mismatch between the polymer particle and the adhesive matrix is the main cause of this contact degradation. To understand this phenomenon better, a three-dimensional (3-D) finite element (FE) model of an ACF joint has been analyzed in order to predict the stress distribution in the conductive particles, adhesive matrix and metal pads during the reflow process. The stress level at the interface between the particle and its surrounding materials is significant and it is the highest at the interface between the particle and the adhesive matrix.

The use of fluorescence microscopy to define polymer localisation to the late endocytic compartments in cells that are targets for drug delivery

Macromolecular therapeutics and nano-sized drug delivery systems often require localisation to specific intracellular compartments. In particular, efficient endosomal escape, retrograde trafficking, or late endocytic/lysosomal activation are often prerequisites for pharmacological activity. The aim of this study was to define a fluorescence microscopy technique able to confirm the localisation of water-soluble polymeric carriers to late endocytic intracellular compartments. Three polymeric carriers of different molecular weight and character were studied: dextrin (Mw~50,000 g/mol), a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer (Mw approximately 35,000 g/mol) and polyethylene glycol (PEG) (Mw 5000 g/mol). They were labelled with Oregon Green (OG) (0.3-3 wt.%; <3% free OG in respect of total). A panel of relevant target cells were used: THP-1, ARPE-19, and MCF-7 cells, and primary bovine chondrocytes (currently being used to evaluate novel polymer therapeutics) as well as NRK and Vero cells as reference controls. Specific intracellular compartments were marked using either endocytosed physiological standards, Marine Blue (MB) or Texas-red (TxR)-Wheat germ agglutinin (WGA), TxR-Bovine Serum Albumin (BSA), TxR-dextran, ricin holotoxin, C6-7-nitro-2,1,3-benzoxadiazol-4-yl (NBD)-labelled ceramide and TxR-shiga toxin B chain, or post-fixation immuno-staining for early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins (LAMP-1, Lgp-120 or CD63) or the Golgi marker GM130. Co-localisation with polymer-OG conjugates confirmed transfer to discreet, late endocytic (including lysosomal) compartments in all cells types. The technique described here is a particularly powerful tool as it circumvents fixation artefacts ensuring the retention of water-soluble polymers within the vesicles they occupy.