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Early Experiments at FAIR in 2018 - 2022 suggested by the HEDgeHOB collaboration in the field of non-ideal plasma physics are discussed. Specific energies of 5-10 kJ/g, pressures of 1-2 GPa and temperatures of 1-2 eV are expected to be reached in the substance at the first experiments with a U+28 beam with the energy of 0.2 AGeV and maximal intensity 3 · 1010 per impulse. It will provide the possibility to investigate the two phase region including the critical point of several metals in HIHEX (Heavy Ion Heating and EXpansion) experiments with the plane and cylindrical geometry, realizing regimes of quasi-isochoric heating, isentropic expansion and compression when the flow strikes the target. Analysis of thermal radiation transfer will give information on the vaporization dynamics. Measurements of electrical conductivity and optical properties on the supercritical adiabat will disclose information on the insulator to metal transition under these conditions. (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Molecular docking is a computational method for predicting the placement of ligands in the binding sites of their receptor(s). In this review, we discuss the methodological developments that occurred in the docking field in 2012 and 2013, with a particular focus on the more difficult aspects of this computational discipline. The main challenges and therefore focal points for developments in docking, covered in this review, are receptor flexibility, solvation, scoring, and virtual screening. We specifically deal with such aspects of molecular docking and its applications as selection criteria for constructing receptor ensembles, target dependence of scoring functions, integration of higher-level theory into scoring, implicit and explicit handling of solvation in the binding process, and comparison and evaluation of docking and scoring methods.

Human small molecule metabolites (the human metabolome) are a set of compounds that interact with at least one macromolecule in the biosphere. This study investigates the acid/base profile of the human metabolome, natural products and drugs, together with an analysis of their physicochemical properties. Ionisation constants (pKa values) are estimated for each compound and the identity of the ionisable functional groups in each set is determined. The acid/base and physicochemical property profile of the lipid component of the metabolome differed considerably to the other datasets. In contrast, the acid/base properties of non-lipid metabolites were found to be similar to both drugs and natural products. While the non-lipid metabolites have lower average ClogP values and more hydrogen bond donors than the other datasets, the distribution of physicochemical property values overlapped considerably with the drug dataset. Considering also that the non-lipid metabolites are of biochemical interest, their characteristics have great potential to influence the selection of screening compounds for drug discovery.

The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the strength of binding. We discuss, in detail, methodological developments that occurred in the docking field in 2010 and 2011, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. The main developments in docking in this period, covered in this review, are receptor flexibility, solvation, fragment docking, postprocessing, docking into homology models, and docking comparisons. Several new, or at least newly invigorated, advances occurred in areas such as nonlinear scoring functions, using machine-learning approaches. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design. Where appropriate, we refer readers to exemplar case studies.

Mutations of peptides to generate altered peptide ligands, capable of switching immune responses from T helper 1 (Th1) to T helper 2 (Th2), are promising candidates for the immunotherapy of autoimmune diseases such as multiple sclerosis (MS). We synthesized two mutant peptides from myelin basic protein 87-99 (MBP(87-99)), an immunodominant peptide epitope identified in MS. Mutations of residues K(91) and P(96), known to be critical T-cell receptor (TCR) contact sites, resulted in the mutant peptides [R(91), A(96)]MBP(87-99) and [A(91), A(96)]MBP(87-99). Immunization of mice with these altered peptide ligands emulsified in complete Freund's adjuvant induced both interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) responses compared with only IFN-gamma responses induced to the native MBP(87-99) peptide. It was of interest that [R(91), A(96)]MBP(87-99) conjugated to reduced mannan induced 70% less IFN-gamma compared with the native MBP(87-99) peptide. However, [A(91), A(96)]MBP(87-99) conjugated to reduced mannan did not induce IFN-gamma-secreting T cells, but elicited very high levels of interleukin-4 (IL-4). Furthermore, antibodies generated to [A(91), A(96)]MBP(87-99) peptide conjugated to reduced mannan did not cross-react with the native MBP(87-99) peptide. By molecular modelling of the mutant peptides in complex with major histocompatibility complex (MHC) class II, I-A(s), novel interactions were noted. It is clear that the double-mutant peptide analogue [A(91), A(96)]MBP(87-99) conjugated to reduced mannan is able to divert immune responses from Th1 to Th2 and is a promising mutant peptide analogue for use in studies investigating potential treatments for MS.

Lewis system carbohydrate antigens have been shown to be expressed at high levels in many cancers of epithelial cell origin, including those of colon, breast, lung, prostate and ovary. The type 1 (Le(a) and Le(b)) antigens are important histo-blood groups, while type 2 (Le(x) and Le(y)) antigens in healthy individuals are only expressed, at relatively low levels, by a few tissues, including some epithelial cells. Thus, the type 2 antigens are considered to be tumour-associated antigens and are promising targets for cancer treatment, including antibody-based immunotherapy. In this review, we discuss the conformational characteristics of the free and bound forms of Lewis oligosaccharides and the 3D structures of antibodies in complex with Le(y) and Le(x) antigens. Collectively, the structural studies have demonstrated that the Lewis determinants are rigid structures, which generally maintain the same conformation in the free and bound states. The rigid nature and similarities in shape of type 1 and 2 Lewis oligosaccharides appear to make them perfectly suited to driving a structurally convergent immune response (at least in the case of Le(y) specific antibodies) toward a highly specific recognition of individual carbohydrate determinants, which is a goal in the development of effective antibody-based cancer treatments.

Mcg light chain dimer has been extensively studied by crystallography and peptide binding studies to investigate its peptide cross-reactivity as well as to use it as a model system for designing space filling peptide ligands. Here we extend these investigations by utilizing automated docking. Mcg light chain dimer is an ideal model system for such study due to the availability of experimental data for both the native structure and the 14 complexes with various peptide ligands. We show the ability of the docking approach to reproduce the experimental structures and discuss the limitations associated with such outcomes. We demonstrate the usefulness of the docking approach in generating structural information otherwise not available from the experiment.

A monoclonal IgM cryoglobulin with diverse binding behavior was isolated from a patient (Mez) with Waldenstrom's macroglobulinemia. It gave very high titers in the binding of combinatorially synthesized libraries of peptides ranging in size from two to eight residues. The crystal structure of Mez Fv revealed that the binding site was divided into two cavities of unequal volumes with dimensions and chemical properties that were compatible with the binding of peptides. Access to this unique combination of structural information and peptide binding data led us to carry out Mez-peptide docking simulations to gain insight into the Mez binding propensities. In the present article, the results for docking of five peptide libraries are combined with discussions of the methods and approximations involved in the docking process. We analyze the origins of peptide binding affinity for Mez IgM in terms of its cross-reactivity and its structural preferences. Copyright © 2001 John Wiley & Sons, Ltd. Abbreviations used: 3-D three-dimensional Ab antibody A absorbance C constant CDR complementarity-determining region CH constant domain of the heavy chain ELISA enzyme-linked immunosorbent assay Fv fragment variable H heavy HB hydrogen bond L light PDB Protein Data Bank V variable VH variable region of the heavy chain VL variable region of the light chain vdW van der Waals

While drug discovery scientists take heed of various guidelines concerning drug-like character, the influence of acid/base properties often remains under-scrutinised. Ionisation constants (pKa values) are fundamental to the variability of the biopharmaceutical characteristics of drugs and to underlying parameters such as logD and solubility. pKa values affect physicochemical properties such as aqueous solubility, which in turn influences drug formulation approaches. More importantly, absorption, distribution, metabolism, excretion and toxicity (ADMET) are profoundly affected by the charge state of compounds under varying pH conditions. Consideration of pKa values in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery. Given the recent low annual output of new drugs from pharmaceutical companies, this review will provide a timely reminder of an important molecular property that influences clinical success.

Cell surface glycoproteins play vital roles in cellular homeostasis and disease. Antibody recognition of glycosylation on different cells and pathogens is critically important for immune surveillance. Conversely, adverse immune reactions resulting from antibody−carbohydrate interactions have been implicated in the development of autoimmune diseases and impact areas such as xenotransplantation and cancer treatment. Understanding the nature of antibody−carbohydrate interactions and the method by which saccharides fit into antibody binding sites is important in understanding the recognition process. In silico techniques offer attractive alternatives to experimental methods (X-ray crystallography and NMR) for the study of antibody−carbohydrate complexes. In particular, molecular docking provides information about protein−ligand interactions in systems that are difficult to study with experimental techniques. Before molecular docking can be used to investigate antibody−carbohydrate complexes, validation of an ...

Zhou and Levery raise several issues related to our work1 that we would like to address. First, these authors are concerned with the specificity of the mAb 15.101. In the first paragraph of page 627, we state ‘Thus, we can conclude that all the mAbs can bind to Galα(1,3)Gal antigens produced by α1,3GT (protein and lipid) and iGb3S (lipid) on the cell surface. However, of all the antibodies studied, 15.101 binds cell surface expressed Galα(1,3)Gal produced by α1,3GT only weakly, whereas it binds intensely to Galα(1,3)Gal produced by iGb3S (that is, iGb3).’ Zhou and Levery criticize the claim that 15.101 can indeed identify iGb3. They correctly state that iGb3 synthase (iGb3S), the enzyme that generates iGb3, also produces poly-α-Gal glycosphingolipids (GSL) using iGb3, Gb3, iGb4 and Gb4 as substrates.2, 3 We have published data that clearly show that the mAb 15.101 does indeed bind to purified iGb3 in ELISA assays.4 Furthermore, we have thin layer chromatography data showing 15.101 binding to both iGb3 and poly-α-Gal GSL (data not shown). Thus, this mAb can detect all forms of Galα(1,3)Gal produced by iGb3S. Accordingly, we should have stated ‘binds intensely to Galα(1,3)Gal produced by iGb3S (including iGb3).’

A new variational principle for the probability of forbidden transitions is derived. Upper and lower bounds for the corresponding matrix element are given. On etablit une nouvelle methode variationelle pour calculer la probabilite de transitions defendues, ainsi que des bornes superieures etinferieures del'element matriciel correspondant. Ein neues Variationsprinzip fur die Wahrscheinlichkeit verbotener Ubergange wird angegeben. Man erhalt auch obere und untere Grenzen fur das entsprechende Matrixelement.

The NMR relaxation times T1 and T2 for starch polysaccharides in solution were employed for the characterization of bound and free water. The “Solomon equations” were taken for the calculation of the amount of bound water in maltodextrin-water systems. The amount of monomolecular bound water in maltodextrin solutions and gels is independent on the state in the same order of magnitude as estimated for maltodextrin powders from water vapour sorption isotherms. With increasing temperature between 1°C and 60°C a slight decrease of bound water was found. NMR-Untersuchung des gebundenen Wassers in Maltodextrin-Wasser-Systemen. Die NMR-Relaxationszeiten T1 und T2 fur Starkepolysaccharide in Losung wurden zur Charakterisierung des freien und gebundenen Wassers herangezogen. Zur Berechnung des Anteils an gebundenem Wasser in Maltodextrin-Wasser-Systemen wurden die „Solomonschen Gleichungen” verwendet. Der Anteil an monomolekular gebundenem Wasser in Maltodextrinlosungen und -gelen liegt zustandsunabhangig in der gleichen Grosenordnung, wie er fur Maltodextrinpulver aus den Wassersorptionsisothermen bestimmt wurde. Mit steigender Temperatur zwischen 1°C und 60°C erfolgt eine geringe Abnahme des Anteils an gebundenem Wasser.