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The presence of amyloid is a hallmark of Gerstmann-Straussler-Scheinker (GSS) disease, which is a prion disease caused by germ line mutations in the PRNP gene. The major component of amyloid is a fragment spanning residues from 81-82 to 144-153, part of the minimal sequence thought to play a crucial role in the conversion reaction and to sustain prion replication. We present here a molecular dynamics study on the 82-146 peptide from the human prion protein. The aim is to identify its aggregation-prone folds. The 82-146 prion sequence corresponds to a naturally occurring prion peptide able to form fibrils rich in parallel beta-sheets. A spontaneous right-handed beta-helical arrangement with 13 residues per turn can be observed in the 103-135 segment of the 82-146 peptide. The observed fold is in accordance with the evidence of a parallel beta-sheet organization in amyloid and with experiments on 82-146 discussed in the literature. To elucidate the conformational properties that trigger this peptide’s aggregation propensity, the conformational behavior of peptides of different length (106-126 and 113-120 prion segments) was also investigated. Simulation analysis has led to some interesting considerations on sequence specific flexibility and the effects of growth. Comparing peptides of different length allows the localization of the origin of the beta-helix conformational propensity in the 106-126 segment, though longer sequences appear necessary for a clear beta-helical arrangement. Structural features of the observed 82-146 beta-helical fold are compatible with the ‘‘dock and lock’’ mechanism proposed to interpret peptide aggregation kinetics.

There is evidence that Tetracyclines are potentially useful drugs to treat prion disease, the fatal neurodegenerative disease in which cellular prion proteins change in conformation to become a disease-specific species (PrPSc). Based on an in vitro anti-fibrillogenesis test, and using the peptide PrP106-126 in the presence of tetracycline and 14 derivatives, we carried out a three-dimensional quantitative structure-activity relationship (3D-QSAR) study to investigate the stereoelectronic features required for anti-fibrillogenic activity. A preliminary variable reduction technique was used to search for grid points where statistical indexes of interaction potential distributions present local maximum (or minimum) values. Variable selection genetic algorithms were then used to search for the best 3D-QSAR models. A 6-variable model showed the best predictability of the anti-fibrillogenic activity that highlighted the best tetracycline substitution patterns: hydroxyl group presence in positions 5 and 6, electrodonor substituents on the aromatic D-ring, alkylamine substituent at the amidic group in position 2 and non-epi configuration of the NMe2 group. © Springer-Verlag 2008.

Computational approaches based on Molecular Dynamics simulations, Quantum Mechanical methods and 3D Quantitative Structure-Activity Relationships were employed by computational chemistry groups at the University of Milano-Bicocca to study biological processes at the molecular level. The paper reports the methodologies adopted and the results obtained on Aryl hydrocarbon Receptor and homologous PAS proteins mechanisms, the properties of prion protein peptides, the reaction pathway of hydrogenase and peroxidase enzymes and the defibrillogenic activity of tetracyclines. © Springer-Verlag 2007.

Extensive molecular dynamic simulations (similar to 240 ns) have been used to investigate the conformational behavior of PrP106-126 prion peptide in four different environments (water, dimethyl sulfoxide, hexane, and trifluoroethanol) and under both neutral and acidic conditions. The conformational polymorphism of PrP106-126 in solution observed in the simulations supports the role of this fragment in the structural transition of the native to the abnormal form of prion protein in response to changes in the local environmental conditions. The peptide in solution is primarily unstructured. The simulations show an increased presence of helical structure in an apolar solvent, in agreement with the results from circular dichroism spectroscopy. In water solution, beta-sheet elements were observed between residues 108-112 and either residues 115-121 or 121-126. An alpha-beta transition was observed under neutral conditions. In DMSO, the peptide adopted an extended conformation, in agreement with nuclear magnetic resonance experiments.

The conformational behavior in aqueous solution of four complexes of the Eu(III) ion with bis (R-amide) derivatives (R = H, methyl, ethyl, butyl) of diethylentriamine pentacetate ligands has been characterized at the ab initio level to rationalize the experimentally observed influence of alkyl substituents on the rate of the exchange process of the water molecule coordinated to the ion with the bulk water. Calculations were performed in vacuo and for aqueous solution, the latter by using the polarizable continuum model. Geometry optimizations provide, for each system, four isomers as stable conformations, all presenting a distorted tricapped trigonal prism coordination geometry around the ion. No significant influence of the alkyl substitution on the coordination geometry, nor on the europium-water distance, was observed. Moreover, increasing the length of the alkyl chain had no significant effect on the relative isomer population in solution. Thus, these results lead us to suppose that other effects, like those deriving from lateral chain folding in solution, should be considered to explain the increased rate of the water-exchange process with alkyl chain lengthening. © Springer-Verlag 2003.

The dominating route to polychlorinated Dibenzo-p-dioxin and Dibenzofuran formation in the ‘‘cold zones’’ of flue gas cleaning systems of municipal solid waste incinerators is the so-called de novo synthesis, that is, carbonaceous matrix burnoff with simultaneous oxidation and chlorination reactions. Pyrene (1) and Benzodibenzofuran (2) were chosen as the model compounds of carbonaceous material present in fly ash. Possible routes of Dibenzofuran formation by oxidative pathways of compounds (1) and (2) were investigated by theoretical calculations at the density functional theory level. The key intermediate peroxy radical, formed by reaction with molecular oxygen, can follow three main paths leading to Dibenzofuran. In the kinetically favourite path, the highest energetic barriers (25–30 kcal mol-1) are encountered in the steps where CO molecules are released from ketenelike structures. These findings agree with previously reported temperature-programmed desorption results on CO desorption. Moreover, along this path, phenanthrene and biphenyl intermediates are formed, in agreement with the detection of these products in previously reported experimental Pyrene oxidation. Along the preferred path, different steric constraints in compounds (1) and (2) play a role in determining the relative stability of the intermediates, while they have less influence on the energetic barriers. As a consequence, compounds (1) and (2) should present similar kinetic behaviour as they present similar energetic barriers.

The role of multivariate analysis methods in evaluating, rationalizing, and working out complex environmental problems is discussed. The discussion is organized in two sections; a literature analysis of the application of chemometric methods to PCDD/PCDF data interpretation and source correlation and a review of the role of chemometric methods in analysing the results obtained by the Authors studying PCDD/PCDF formation and destruction mechanisms in MSW combustion processes.

The molecular electrostatic potential (MEP) distribution of anisole, chlorobenzene, and fluorobenzene obtained from STO-3G, 3-21G, and 6-31G* basis set ab initio and MNDO and AM1 semiempirical wave functions is investigated to explain the differences among the MEP features obtained for polychlorodibenzo-p-dioxins. The main topological features as well as the absoltue and relative minima location obtained from ab initio calculations are independent from the choice of the basis set. MNDO calculations are in good agreement with the ab initio ones in the case of anisole and fluorobenzene, while they incorrectly describe the MEP of chlorobenzene. The AM1 fails to localize the absolute minimum of fluorobenzene and does not find the minimum above the chlorobenzene chlorine atom. The poor agreement of both semiempirical methods with ab initio for any kind of chlorinated compounds is confirmed by results obtained for chloreothylene and chloroethane. We hypothesize that the main problem concerning these methods is that they freeze a too large amount of electrons in the atomic core of elements belonging to the second row, which makes for a wrong description of the core–valence electron interactions. Results obtained by modifying the AM1 parameters related to these interactions confirm our hypothesis. © 1992 by John Wiley & Sons, Inc.

The conformational behaviour in aqueous solution of the EgadMe complex, a conditional gadolinium-based contrast agent sensitive to beta-galactosidase enzymatic activity, is investigated by means of ab initio calculations and classical molecular dynamics simulations. Furthermore, force field parameterization of gadolinium-ligand interactions is performed, and its reliability is tested on the bench mark [Gd(DOTA)](-) system by MD simulations. Both computational methods highlight the presence in EgadMe of two main conformational isomers. The lowest energy conformation is a "close" form, corresponding to a state of low-relaxivity (MRI "inactive"), in which the ninth coordination site of the gadolinium ion is occupied by one oxygen atom of the galactopyranose residue. The second isomer, which is 2.9 (at ab initio level) and 4.2 (at MD level) kcal mol(-1) above the global minimum, presents an "open" form, corresponding to a state of high-relaxivity (MRI "active") in which one water molecule coordinates the ion. These results are consistent with experimental findings reported for EgadMe, and show that competition at the ninth coordination site of gadolinium ion, between the intra (the galactopyranose residue) and inter (water molecules) molecular interactions, affects the relaxivity of this system.

A model which makes use of the complete perturbative treatment of Salem and Devaquet is proposed for the interpretation of regio-, sito- and stereo-selectivity of cycloaddition reactions. The van der Waals intermolecular interaction potential-energy surface minima relevant to the hypothesized alternative reaction paths are suggested as model structures (perturbed states) for the corresponding weakly interacting complexes in the early stages of the reaction. It is shown how results are affected by the increase in the degrees of freedom for the approach of the two interacting molecules, by the choice of a particular atom-atom potential and by the two-partner internal-geometry relaxation which occurs at the perturbed state. The results obtained for some sample reactions (butadiene and ethylene, penta-1,3-diene and acrolein, penta-1,3 -diene and 2,5-dimethyl-1,4-benzoquinone) corroborate our previous choice of a Lennard-Jones function and of an undistorted reagent geometry to localize the non-bonding minima. The inclusion of a greater number of intermolecular variables and their simultaneous optimization during the non-bonding minima localization is a marked improvement for the definition of the perturbed state. The results obtained for the reactions of mono- and di-substituted dienes with unsymmetrically substituted quinones confirm the predictive ability of our improved procedure.

Tetracycline (TC) and its derivatives have recently been proposed as a new class of antagonists in prion diseases as they prevent the aggregation of prion protein peptides and their acquisition of protease resistance in vitro and in vivo. Looking for relationships between conformational flexibility and biological activity, we searched for a geometrical pharmacophore by investigating, in aqueous solution, the conformational behavior of 15 TCs in both the zwitterionic and the anionic forms. For TC similar conformational flexibility was found for the two forms and two main conformational families were detected, an extended and a folded conformation characterized by different intramolecular hydrogen-bond networks. On comparing the Molecular Mechanics results with the ab initio ones and the experimental evidence, it can be seen that the conformational behavior of TC is reasonably well predicted by the MM2 force field, whereas the conformational energies provided by the Amber force field are unreliable. The conformational analysis of the other TC derivatives was then performed by the MM2 force field. As a result, their conformational behavior was similar to that observed for TC itself. Despite the hydronaphthacene moiety’s conformational flexibility, no geometrical pharmacophore was found among the TCs, i.e. properties other than geometrical ones should play a crucial role in determining their anti-fibrillogenic ability. Figure Molecular structures of the lowest energy conformations present: i) in clusters a and b (extended conformations); ii) in clusters c and d (folded conformations). Hydrogen atoms not reported, with the exception of the 4-HN(Me)2 one.

The recent design of new magnetic resonance imaging (MR) contrast agents is oriented toward the synthesis of gadolinium(III) complexes with ligands presenting formally neutral (amidic or alcoholic) or anionic (phosphinic) oxygen donor atoms. This paper presents the molecular mechanics (MM) parametrization of Gd interactions with amidic, alcoholic and phosphinic oxygen donor atoms, with the aim of supporting experimental effort. The parametrization is performed on the basis of a previously developed procedure applied to the parametrization of Gd interactions with polyamino carboxylate (PAC) ligands. Within the framework of valence force fields, the parameters for Gd-ligand interactions are determined by fitting the empirical potential to the ab initio potential energy surface (PES) of [Gd . 3 . OH2](3+), [Gd . 5b . OH2](3+), and [Gd . 8a](1-). Ab initio calculations were performed at the restricted Hartree-Fock (RHF) level by using an effective core potential (ECP) that includes 4f electrons in the core, an optimized valence basis set for the metal, and the 3-21G basis set for the ligand. Sampling of the PES is performed by moving the ion into the frozen coordination cage of the ab initio optimized geometries, The energy and first derivatives, with respect to the Cartesian coordinates of the metal and donor atoms, were calculated for each generated structure. Two sets of parameters, with the electrostatic contribution turned on or off in the force fields, were determined. To test the quality of the derived parameters and their transferability to other Gd complexes, MM calculations were performed on several gadolinium complexes. The results show that both sets of parameters provide reliable molecular geometries, but it is necessary to include the electrostatic contribution in the force fields to correctly reproduce the conformational energies

Experimental data on PCDD and PCDF emissions in raw gases from municipal solid waste combustion in a pilot plant were processed by Response Surface models to gain information on process parameter values which minimize both the total PCDD/PCDF concentrations and those of a selected congener group.

The conformational features of ten known amnesia reversal compounds were analyzed by the molecular mechanics calculations with the aim of identifying a common spatial disposition of the polar functional groups present in all the molecules (a N‐C=O amidic group and a X‐C=O group, with X = O, N). Principal component analysis (PCA) led to the identification of three interatomic distances able to provide all the information necessary to describe the relative spatial disposition of the two functional groups. Cluster analysis was then performed to group the minimum energy conformations according to the values of those distances. Clusters were analyzed to single out those containing conformations of the maximum number of active compounds. This procedure permitted the finding of several acceptable pharmacophore models. The influence on results by the dissociated/undissociated forms of carboxylic compounds presented in the data set is also discussed. Two potent prolyl endopeptidase (PEP) inhibitors showing strong anti‐amnesic effect were also included in the study. The results suggest that the common biological activity between these classes of compounds could be interpreted on the basis of the common spatial disposition of the investigated functional groups. Copyright © 1990 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Literature data on the presence of PCDDs and PCDFs in the feeding and in the emissions of municipal solid waste incinerators were analysed and are discussed in relation to possible sources of PCDD and PCDF in MSW, characterization of their profiles in feeding and emissions as well as correlation of PCDD and PCDF total concentrations in the emissions.

Literature data on the presence of PCDDs and PCDFs in the feeding as well as in the emissions of municipal solid waste incinerators have been collected and incorporated in a data base. The presence of PCDDs and PCDFs in MSW and their possible sources are discussed. The congener profiles of PCDD and PCDF have been identified and used as fingerprints for the comparison of the various samples. The possibility that PCDDs and PCDFs present in MSW and RDF come from commercial 5CP, as well as from products which use 5CP or its sodium salt in the manufacturing process, is shown here. © 1989.

A list of papers appeared in the worldwide literature in the period 1970-1987 is reported. The papers are classified according to a list of subjects which outlines the most significant aspects in the study of PCDD and PCDF formation.

Literature data on PCDD and PCDF emissions in stack gas from municipal solid waste incinerators were analysed and are discussed in relation to the combustion temperature and the particulate/condensate distribution. Principal component analysis allows the definition of the fingerprints of PCDD and PCDF in stack gas. The analysis of correlations between the percentage distributions of dioxin or furan congeners suggests a possible reaction mechanism. A linear correlation between PCDF and PCDD total concentrations has been made evident. The role of MSW as a source of dioxins and furans in these emissions is discussed. © 1989.