Free energy calculations of glycosaminoglycan - Protein interactions

Glycosaminoglycans (GAGs) are complex highly charged linear polysaccharides that have a variety of roles in biological processes. We report the first use of molecular dynamics (MD) free energy calculations using the MM/PBSA method to investigate the binding of GAGs to protein molecules, namely the platelet endothelial cell adhesion molecule 1 (PECAM-1) and annexin A2. Calculations of the free energy of the binding of heparin fragments of different sizes reveal the existence of a region of low GAG-binding affinity in domains 5-6 of PECAM-1 and a region of high affinity in domains 2-3, consistent with experimental data and ligand-protein docking studies. A conformational hinge movement between domains 2 and 3 was observed, which allows the binding of heparin fragments of increasing size (pentasaccharides to octasaccharides) with an increasingly higher binding affinity. Similar simulations of the binding of a heparin fragment to annexin A2 reveal the optimization of electrostatic and hydrogen bonding interactions with the protein and protein-bound calcium ions. In general, these free energy calculations reveal that the binding of heparin to protein surfaces is dominated by strong electrostatic interactions for longer fragments, with equally important contributions from van der Waals interactions and vibrational entropy changes, against a large unfavorable desolvation penalty due to the high charge density of these molecules.

Free energy calculations of the interactions of c-Jun-based synthetic peptides with the c-Fos protein

The c-Fos–c-Jun complex forms the activator protein 1 transcription factor, a therapeutic target in the treatment of cancer. Various synthetic peptides have been designed to try to selectively disrupt the interaction between c-Fos and c-Jun at its leucine zipper domain. To evaluate the binding affinity between these synthetic peptides and c-Fos, polarizable and nonpolarizable molecular dynamics (MD) simulations were conducted, and the resulting conformations were analyzed using the molecular mechanics generalized Born surface area (MM/GBSA) method to compute free energies of binding. In contrast to empirical and semiempirical approaches, the estimation of free energies of binding using a combination of MD simulations and the MM/GBSA approach takes into account dynamical properties such as conformational changes, as well as solvation effects and hydrophobic and hydrophilic interactions. The predicted binding affinities of the series of c-Jun-based peptides targeting the c-Fos peptide show good correlation with experimental melting temperatures. This provides the basis for the rational design of peptides based on internal, van der Waals, and electrostatic interactions.

Calculations of the free energy of interaction of the c-Fos−c-Jun coiled coil: Effects of the solvation model and the inclusion of polarization effects

The leucine zipper region of activator protein-1 (AP-1) comprises the c-Jun and c-Fos proteins and constitutes a well-known coiled coil protein−protein interaction motif. We have used molecular dynamics (MD) simulations in conjunction with the molecular mechanics/Poisson−Boltzmann generalized-Born surface area [MM/PB(GB)SA] methods to predict the free energy of interaction of these proteins. In particular, the influence of the choice of solvation model, protein force field, and water potential on the stability and dynamic properties of the c-Fos−c-Jun complex were investigated. Use of the AMBER polarizable force field ff02 in combination with the polarizable POL3 water potential was found to result in increased stability of the c-Fos−c-Jun complex. MM/PB(GB)SA calculations revealed that MD simulations using the POL3 water potential give the lowest predicted free energies of interaction compared to other nonpolarizable water potentials. In addition, the calculated absolute free energy of binding was predicted to be closest to the experimental value using the MM/GBSA method with independent MD simulation trajectories using the POL3 water potential and the polarizable ff02 force field, while all other binding affinities were overestimated.

Atomistic investigation into the mechanical behaviour of crystalline and amorphous TiO2 nanotubes

Titanium dioxide (TiO2) nanotubes are appealing to research communities due to their excellent functional properties. However, there is still a lack of understanding of their mechanical properties. In this work, we conduct molecular dynamics (MD) simulations to investigate the mechanical behaviour of rutile and amorphous TiO2 nanotubes. The results indicate that the rutile TiO2 nanotube has a much higher Young's modulus (∼800 GPa) than the amorphous one (∼400 GPa). Under tensile loading, rutile nanotubes fail in the form of brittle fracture but significant ductility (up to 30%) has been observed in amorphous nanotubes. This is attributed to a unique ‘repairing’ mechanism via bond reconstruction at under-coordinated sites as well as bond conversion at over-coordinated sites. In addition, it is observed that the fracture strength of rutile nanotubes is strongly dependent on their free surfaces. These findings are considered to be useful for development of TiO2 nanostructures with improved mechanical properties.

New perspectives on design and delivery: The context of service desk

This research has identified the trends apparent in service desk design and delivery literature. By doing archival analysis, this investigation has led to the development of a generic framework which has identified three themes in service desk design – User groups, Support models, and Technology types – and two themes in service desk delivery – Direction of delivery, and Executive support level. This research also aims to provide an understanding of service desk functions and the challenges faced by organisations in delivering those functions.

Novel synthesis of superparamagnetic Ni-Co-B nanoparticles and their effect on superconductor properties of MgB2

A new procedure for the preparation of amorphous Ni-Co-B nanoparticles is reported, with a detailed investigation of their morphology by X-ray diffraction and transmission electron microscopy, as well as their magnetic properties. Many factors, such as chemical composition, anisotropy, size and shape of the particles, were controlled through chemical synthesis, resulting in the control of morphological and magnetic properties of the nanoparticles. Controlling pH values with ethylenediamine and using sodium dodecyl sulfate surfactant lowered the size of the nanoparticles to below 10 nm. Such a small structure and chemical disorder in nanocrystalline materials lead to magnetic properties that are different from those in their bulk-sized counterparts. The obtained nanoparticles can be used for different purposes, from pharmaceutical applications to implementations in different materials technology. The focus of this research is the synthesis of Ni-Co-B nanoparticles in a new way and studying the reaction of Ni-Co-B nanoparticles with Mg and B precursors and their effect on MgB2 properties. New nanostructures are formed in the reaction of Ni-Co-B nanoparticles with Mg: Mg2Ni, Co2Mg and possibly Mg2Co.

Relationship between quality certification and financial and non-financial performance of organizations

At present, many countries have either embraced ISO9001 or used it as the basis of their national quality certification systems. However, few studies have been conducted to examine the benefits companies’ gain from achieving and implementing ISO9001 standards (Chikuku et al. 2012; Psomas et al. 2013; Sampaio et al. 2011a,b). Analysis has brought much more confused and uneven results across the countries. Turning to the experience of Malaysia, this country has witnessed a spectacular growth at an average rate of 9.89% per annum of ISO certificates issued to companies operating within its borders (ISO Survey 2012). While many companies rush to be ISO 9001 certified whether this brings about better benefits (both the financial and the non-financial) is still an open question. In this study, the research problems were first formulated from the literature and then a questionnaire survey was conducted to test the hypotheses. A survey was administered to chief executives officers and managers across manufacturing and service organizations in Malaysia. Multivariate analysis and SPSS macro developed by Preacher and Hayes were used as statistical techniques to the financial and non-financial benefits of ISO9001 certification. The survey instrument was a two-page questionnaire comprising three sections. The first section of the questionnaire covered the company’s profile. The second section consisted of 25 items on internal benefits and third section consisted of 7 items on external benefits measured on 1–5 Likert scale to assess the benefits of ISO9001 certification. Total 201 valid responses were received. Results of the study indicate that there was no significant direct relationship between ISO9001 certification and organizational financial performance, while strong statistical evidence was found to support the direct relationship between ISO9001 certification and non-financial performance. The findings of the study discovered that financial performance is actually directly related to two non-financial measures, namely quality performance and local and international business performance, which are directly and significantly influenced by ISO9001 certification. Therefore non-financial performance measures are involved in the mediational process. The findings will assist practitioners in taking right courses of action that make the implementation of this standard more effective. For example, the study findings study suggests that companies should put emphasize on nonfinancial factors to improve their financial performance.

Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition

Laskowski inhibitors regulate serine proteases by an intriguing mode of action that involves deceiving the protease into synthesizing a peptide bond. Studies exploring naturally occurring Laskowski inhibitors have uncovered several structural features that convey the inhibitor's resistance to hydrolysis and exceptional binding affinity. However, in the context of Laskowski inhibitor engineering, the way that various modifications intended to fine-tune an inhibitor's potency and selectivity impact on its association and dissociation rates remains unclear. This information is important as Laskowski inhibitors are becoming increasingly used as design templates to develop new protease inhibitors for pharmaceutical applications. In this study, we used the cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), as a model system to explore how the inhibitor's sequence and structure relate to its binding kinetics and function. Using enzyme assays, MD simulations and NMR spectroscopy to study SFTI variants with diverse sequence and backbone modifications, we show that the geometry of the binding loop mainly influences the inhibitor's potency by modulating the association rate, such that variants lacking a favourable conformation show dramatic losses in activity. Additionally, we show that the inhibitor's sequence (including both the binding loop and its scaffolding) influences its potency and selectivity by modulating both the association and the dissociation rates. These findings provide new insights into protease inhibitor function and design that we apply by engineering novel inhibitors for classical serine proteases, trypsin and chymotrypsin and two kallikrein-related peptidases (KLK5 and KLK14) that are implicated in various cancers and skin diseases.

Comparison of the sensitivity of different sensor technologies to imbalance severity in low speed wind turbines

Imbalance is not only a direct major cause of downtime in wind turbines, but also accelerates the degradation of neighbouring and downstream components (e.g. main bearing, generator). Along with detection, the imbalance quantification is also essential as some residual imbalance always exist even in a healthy turbine. Three different commonly used sensor technologies (vibration, acoustic emission and electrical measurements) are investigated in this work to verify their sensitivity to different imbalance grades. This study is based on data obtained by experimental tests performed on a small scale wind turbine drive train test-rig for different shaft speeds and imbalance levels. According to the analysis results, electrical measurements seem to be the most suitable for tracking the development of imbalance.