Glycogen phosphorylase inhibitors: a free energy perturbation analysis of glucopyranose spirohydantoin analogues

GP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes mellitus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands, estimated by kinetic measurements of the ligand inhibition constants. The calculated binding affinity for methyl-hydan (relative to hydan) is 3.75 +/- 1.4 kcal/mol, in excellent agreement with the experimental value (3.6 +/- 0.2 kcal/mol). For n-hydan, the calculated value is 1.0 +/- 1.1 kcal/mol, somewhat smaller than the experimental result (2.3 +/- 0.1 kcal/mol). A free energy decomposition analysis shows that hydan makes optimum interactions with protein residues and specific water molecules in the catalytic site. In the other two ligands, structural perturbations of the active site by the additional methyl- or amino group reduce the corresponding binding affinities. The computed binding free energies are sensitive to the preference of a specific water molecule for two well-defined positions in the catalytic site. The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated. The results provide insights into the role of water molecules in modulating ligand binding affinities. A comparison of the interactions between a set of ligands and their surrounding groups in X-ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands. For the systems in this work, such an approach fails to estimate the order of relative binding strengths, in contrast to the rigorous free energy treatment.

Design, synthesis and computational modelling of aromatic tweezer-molecules as models for chain-folding polymer blends

Novel 'tweezer-type' complexes that exploit the interactions between pi-electron-rich pyrenyl groups and pi-electron deficient diimide units have been designed and synthesised. The component molecules leading to complex formation were accessed readily from commercially available starting materials through short and efficient syntheses. Analysis of the resulting complexes, using the visible charge-transfer band, revealed association constants that increased sequentially from 130 to 11,000 M-1 as increasing numbers of pi-pi-stacking interactions were introduced into the systems. Computational modelling was used to analyse the structures of these complexes, revealing low-energy chain-folded conformations for both components, which readily allow close, multiple pi-pi-stacking and hydrogen bonding to be achieved. In this paper, we give details of our initial studies of these complexes and outline how their behaviour could provide a basis for designing self-healing polymer blends for use in adaptive coating systems. (C) 2008 Elsevier Ltd. All rights reserved.

Design and theoretical study of nickel catalysts for syndiotactic polyolefins

A nickel catalyst was modeled with ligand L-2, [ NH = CH-CH = CH-O](-), which should have potential use as a syndiotactic polyolefin catalyst, and the reaction mechanism was studied by theoretical calculations using the density functional method at the B3LYP/ LANL2MB level. The mechanism involves the formation of the intermediate [(NiLMe)-Me-2](+), in which the metal occuples a T-shaped geometry. - This intermediate has two possible structures with the methyl group trans either to the oxygen or to the nitrogen atom of L-2. The results show that both structures can lead to the desired product via similar reaction paths, A and B. Thus, the polymerization could be considered as taking place either with the alkyl group occupying the position trans to the Ni-O or trans to the Ni-N bond in the catalyst. The polymerization process thus favors the catalysis of syndiotactic polyolefins. The syndiotactic synthesis effects could also be enhanced by variations in the ligand substituents. From energy considerations, we can conclude that it is more favorable for the methyl group to occupy the trans-O position to form a complex than to occupy the trans-N position. From bond length considerations, it is also more favoured for ethene to occupy the trans-O position than to occupy the trans-N position.

A multicriteria lifespan energy efficiency approach to intelligent building assessment

This paper presents a multicriteria decision-making model for lifespan energy efficiency assessment of intelligent buildings (IBs). The decision-making model called IBAssessor is developed using an analytic network process (ANP) method and a set of lifespan performance indicators for IBs selected by a new quantitative approach called energy-time consumption index (ETI). In order to improve the quality of decision-making, the authors of this paper make use of previous research achievements including a lifespan sustainable business model, the Asian IB Index, and a number of relevant publications. Practitioners can use the IBAssessor ANP model at different stages of an IB lifespan for either engineering or business oriented assessments. Finally, this paper presents an experimental case study to demonstrate how to use IBAssessor ANP model to solve real-world design tasks.

The practice of sustainable facilities management: Design sentiments and the knowledge chasm

The construction industry with its nature of project delivery is very fragmented in terms of the various processes that encompass design, construction, facilities and assets management. Facilities managers are in the forefront of delivering sustainable assets management and hence further the venture for mitigation and adaptation to climate change. A questionnaire survey was conducted to establish perceptions, level of commitment and knowledge chasm in practising sustainable facilities management (FM). This has significant implications for sustainable design management, especially in a fragmented industry. The majority of questionnaire respondents indicated the importance of sustainability for their organization. Many of them stated that they reported on sustainability as part of their organization annual reporting with energy efficiency, recycling and waste reduction as the main concern for them. The overwhelming barrier for implementing sound, sustainable FM is the lack of consensual understanding and focus of individuals and organizations about sustainability. There is a knowledge chasm regarding practical information on delivering sustainable FM. Sustainability information asymmetry in design, construction and FM processes render any sustainable design as a sentiment and mere design aspiration. Skills and training provision, traditionally offered separately to designers and facilities managers, needs to be re-evaluated. Sustainability education and training should be developed to provide effective structures and processes to apply sustainability throughout the construction and FM industries coherently and as common practice.

An investigation of the existing situation and trends in building energy efficiency management in China

According to the Chinese State Council's "Building Energy Efficiency Management Ordinance", a large-scale investigation of energy efficiency (EE) in buildings in contemporary China has been carried out in 22 provincial capitals and major cities in China. The aim of this project is to provide reliable information for drawing up the "Decision on reinforcing building energy efficiency" by the Ministry of Construction of China. The surveyed organizations include government departments, research institutions, property developers, design institutions, construction companies, construction consultancy services companies, facility management departments, financial institutions and those which relate to the business of building energy efficiency. In addition, representatives of the media and residents were also involved. A detailed analysis of the results of the investigation concerning aspects of the cur-rent situation and trends in building energy consumption, energy efficiency strategy and the implementation of energy efficiency measures has been conducted. The investigation supplies essential information to formulate the market entrance policy for new buildings and the refurbishment policy for existing buildings to encourage the development of energy efficient technology.

Planning the sustainable eco-city in Taipei: The implementation of green design and green building schemes

Taipei City has put a significant effort toward the implementation of green design and green building schemes towards a sustainable eco-city. Although some of the environmental indicators have not indicated significant progress in environmental improvement, implementing the two schemes has obtained considerable results; therefore, the two schemes are on the right path towards promoting a sustainable eco-city. However, it has to be admitted that the two schemes are a rather “technocratic” set of solutions and eco-centric approach. It is suggested that not only the public sector but also the private sector need to put more effort toward implement the schemes, and the government needs to encourage the private sector to adopt the schemes in practice.

Urbanisation and its impact on building energy consumption and efficiency in China

The People's Republic of China and its 1.3 billion people have experienced a rapid economic growth in the past two decades. China's urbanisation ratio rose from around 20% in the early 1980s to 45% in 2007 [China Urban Research Committee. Green building. Beijing: Chinese Construction Industrial Publish House; 2008. ISBN 978-7-112-09925-2.]. The large volume and rapid speed of building construction rarely have been seen in global development and cause substantial pressure on resources and the environment. Government policy makers and building professionals, including architects, building engineers, project managers and property developers, should play an important role in enhancing the planning, design, construction, operation and maintenance of the building energy efficiency process in forming the sustainable urban development. This paper addresses the emerging issues relating to building energy consumption and building energy efficiency due to the fast urbanisation development in China.

Design, implementation and testing of an intelligent knowledge-based system for the supervisory control of a hot rolling mill

This paper describes the design, implementation and testing of an intelligent knowledge-based supervisory control (IKBSC) system for a hot rolling mill process. A novel architecture is used to integrate an expert system with an existing supervisory control system and a new optimization methodology for scheduling the soaking pits in which the material is heated prior to rolling. The resulting IKBSC system was applied to an aluminium hot rolling mill process to improve the shape quality of low-gauge plate and to optimise the use of the soaking pits to reduce energy consumption. The results from the trials demonstrate the advantages to be gained from the IKBSC system that integrates knowledge contained within data, plant and human resources with existing model-based systems. (c) 2005 Elsevier Ltd. All rights reserved.

Self-assembled healable materials through a combination of pi-pi stacking and hydrogen bonding

The discovery of polymers with stimuli responsive physical properties is a rapidly expanding area of research. At the forefront of the field are self-healing polymers, which, when fractured can regain the mechanical properties of the material either autonomically, or in response to a stimulus. It has long been known that it is possible to promote healing in conventional thermoplastics by heating the fracture zone above the Tg of the polymer under pressure. This process requires reptation and subsequent re-entanglement of macromolecules across the fracture void, which serves to bridge, and ‘heal’ the crack. The timescale for this mechanism is highly dependent on the molecular weight of the polymer being studied. This process is in contrast to that required to affect healing in supramolecular polymers such as the plasticised, hydrogen bonded elastomer reported by Leibler et al. The disparity in bond energies between the non-covalent and covalent bonds within supramolecular polymers results in fractures propagating through scission of the comparatively weak supramolecular interactions, rather than through breaking the stronger, covalent bonds. Thus, during the healing process the macromolecules surrounding the fracture site only need sufficient energy to re-engage their supramolecular interactions in order to regenerate the strength of the pristine material. Herein we describe the design, synthesis and optimization of a new class of supramolecular polymer blends that harness the reversible nature of pi-pi stacking and hydrogen bonding interactions to produce self-supporting films with facile healable characteristics.

Regression based D-optimality experimental design for sparse kernel density estimation

This paper derives an efficient algorithm for constructing sparse kernel density (SKD) estimates. The algorithm first selects a very small subset of significant kernels using an orthogonal forward regression (OFR) procedure based on the D-optimality experimental design criterion. The weights of the resulting sparse kernel model are then calculated using a modified multiplicative nonnegative quadratic programming algorithm. Unlike most of the SKD estimators, the proposed D-optimality regression approach is an unsupervised construction algorithm and it does not require an empirical desired response for the kernel selection task. The strength of the D-optimality OFR is owing to the fact that the algorithm automatically selects a small subset of the most significant kernels related to the largest eigenvalues of the kernel design matrix, which counts for the most energy of the kernel training data, and this also guarantees the most accurate kernel weight estimate. The proposed method is also computationally attractive, in comparison with many existing SKD construction algorithms. Extensive numerical investigation demonstrates the ability of this regression-based approach to efficiently construct a very sparse kernel density estimate with excellent test accuracy, and our results show that the proposed method compares favourably with other existing sparse methods, in terms of test accuracy, model sparsity and complexity, for constructing kernel density estimates.

Expert system aid for design of overload line distribution networks

The use of expert system techniques in power distribution system design is examined. The selection and siting of equipment on overhead line networks is chosen for investigation as the use of equipment such as auto-reclosers, etc., represents a substantial investment and has a significant effect on the reliability of the system. Through past experience with both equipment and network operations, most decisions in selection and siting of this equipment are made intuitively, following certain general guidelines or rules of thumb. This heuristic nature of the problem lends itself to solution using an expert system approach. A prototype has been developed and is currently under evaluation in the industry. Results so far have demonstrated both the feasibility and benefits of the expert system as a design aid.