Molecular genetics of the NCLs — status and perspectives

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent storage material in many cell types, including neurons. Most NCL subtypes are inherited in an autosomal recessive manner and characterized clinically by epileptic seizures, progressive psychomotor decline, visual failure, variable age of onset, and premature death. To date, seven genes underlying human NCLs have been identified. Most of the mutations in these genes are associated with specific disease subtypes, while some result in variable disease onset, severity and progression. In addition to these, there are still disease subgroups with unknown molecular genetic backgrounds. Although apparent clinical homogeneity exists within some of these subgroups, actual genetic heterogeneity may complicate gene identification. Additional clues to the identification of these unknown genes may come from animal models of NCL and from functional studies of already known genes which may suggest further candidates.     

Immunoglobulin-M purification — Challenges and perspectives

Extensive research in the past two decades has led to the realization of Immunoglobulin-M (IgM) as a potential therapeutic and diagnostic agent. In order to fully exploit the potential of IgM, large quantities, in a highly pure and active form, must be available at low cost for performing clinical trials, characterization studies and quantitative-structure activity analyses. The complex physico–chemical properties, in particular its large size and labile nature renders downstream purification of IgM difficult. This review discusses the limitations and challenges associated with the current IgM purification strategies and proposes future directions for research. The uniqueness of affinity chromatography, specifically biomimetic affinity chromatography for protein purification is highlighted and its potential for IgM purification is discussed.     

River restoration concepts — goals and perspectives

An analysis of restoration projects carried out both in Austria and abroad shows that most projects are limited to design measures within the river bed with the general intention to increase habitat diversity. The various measures are not based on the type-specific characteristics of the river and thus there is a danger of creating uniform restoration stretches, independent of the specific landscape area, river morphology, discharge regime or site specific biocoenoses. Such proceeding lacks in considering a comprehensive improvement of ecological functioning of the whole river-system. To meet those demands a type-specific guiding view (Leitbild) has to be developed based on the pristine river conditions.The comparison of the river pattern including the characteristic features of its unmodified state with the actual situation leads to a comprehensive set of measures. The essential goals of such management-concepts are the integrity of the river habitat, self-regulation and self-regeneration, the preservation of intact resources, as well as the possibility to experience the uniqueness, diversity and beauty of natural river landscapes.     

Disialogangliosides and Their Interaction with Cholera Toxin—Investigation by Molecular Modeling,Molecular Mechanics and Molecular Dynamics

Abstract

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface disialogangliosides (GD1A, GD1B and GD3) in aqueous environment. The molecular mechanics calculation reveals that water mediated hydrogen bonding network plays a significant role in the structural stabilization of GD1A, GD1B and GD3. These water mediated hydrogen bonds not only exist between neighboring residues but also exist between residues that are separated by 2 to 3 residues in between. The conformational energy difference between different conformational states of gangliosides correlates very well with the number of water mediated and direct hydrogen bonds. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin is worked out. The NeuNAc has a limited allowed eulerian space at the binding site of Cholera Toxin (2.4%). The molecular modeling, molecular mechanics and molecular dynamics of disialo- ganglioside-cholera toxin complex reveal that cholera toxin can accommodate the disialo- ganglioside GD1A in three different modes. A single mode of binding is permissible for GD1B and GD3. Direct and water mediated hydrogen bonding interactions stabilizes these binding modes and play an essential role in defining the order of specificity for different disialogangliosides towards cholera toxin. This study not only provides models for the disialoganglioside-cholera toxin complexes but also identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.     

Monosialogangliosides and Their Interaction with Cholera Toxin—Investigation by Molecular Modeling and Molecular Mechanics

Abstract

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface monosialogangliosides (GM3, GM2 and GM1) in aqueous environment. Water mediated hydrogen bonding network plays a significant role in the structural stabilization of GM3, GM2 and GM1. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin reveals a limited allowed eulerian space of 2.4% with a much less allowed eulerian space (1.4%) for external galactose of GM1. The molecular mechanics of monosialoganglioside-cholera toxin complex reveals that cholera toxin can accommodate the monosialogangliosides in three different modes. Direct and water mediated hydrogen bonding interactions stabilize these binding modes and play an essential role in defining the order of specificity for different monosialogangliosides towards cholera toxin. This study identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.     

Conformations of Higher Gangliosides and Their Binding with Cholera Toxin—Investigation by Molecular Modeling,Molecular Mechanics,and Molecular Dynamics

Abstract

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface higher gangliosides (GT1A and GT1B) and their interaction with Cholera Toxin. The water mediated hydrogen bonding network exists between sugar residues in gangliosides. An integrated molecular modeling, molecular mechanics, and molecular dynamics calculation of cholera toxin complexed with GT1A and GT1B reveal that, the active site of cholera toxin can accommodate these higher gangliosides. Direct and water mediated hydrogen bonding interactions stabilize these binding modes and play an essential role in defining the order of specificity for different higher ganglioside towards cholera toxin. This study identifies that the binding site of cholera toxin is shallow and can accommodate a maximum of two NeuNAc residues. The NeuNAc binding site of cholera toxin may be crucial for the design of inhibitors that can prevent the infection of cholera.