PM3-compatible zinc parameters optimized for metalloenzyme active sites

Recent studies have shown that semiempirical methods (e.g., PM3 and AM1) for zinc-containing compounds are unreliable for modeling structures containing zinc ions with ligand environments similar to those observed in zinc metalloenzymes. To correct these deficiencies a reparameterization of zinc at the PM3 level was undertaken. In this effort we included frequency corrected B3LYP/6-311G* zinc metalloenzyme ligand environments along with previously utilized experimental data. Average errors for the heats of formation have been reduced from 46.9 kcal/mol (PM3) to 14.2 kcal/mol for this new parameter set, termed ZnB for "Zinc, Biological." In addition, the new parameter sets predict geometries for the Bacillus fragilis active site model and other zinc metalloenzyme mimics that are qualitatively in agreement with high-level ab initio results, something existing parameter sets failed to do.     

Automated rapid methods in organic elemental analysis

Summary Because of high labour costs, a prerequisite for economic running of an organic elemental analysis laboratory was the development of rapid methods for the most frequently determined elements, which in our case are N, C, H, O, halogens and S. The methods must be capable of automation to the fullest extent, and the analytical results available in the shortest possible time. The data must therefore be presented in digital form for processing by computer, which can (in a fully automated version) print out a complete analytical record. To avoid dependence on physical calibrations, the end-determination methods should yield physical values strictly proportional to the amount of substance. Titration or gas volume measurement seems to fulfil this condition most closely. The methods developed and used at BASF has been reported, along with some new techniques and modifications to apparatus. A crucial point is the possibility of automating the different methods of analysis, and the economics of different degrees of automation have been discussed.

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Zusammenfassung Voraussetzung für die aus Kostenersparnisgründen notwendige Automation elementaranalytischer Labors waren Schnellverfahren für die am häufigsten zu bestimmenden Elemente: in unserem Falle N, C, H, O, Halogene und Schwefel. Die Verfahren müssen weitestgehend automatisierbar sein und die Analysenwerte in möglichst kurzer Zeit zur Verfügung stehen. Die Einzelwerte müssen dabei in digitaler Form vorliegen, um in einem Rechner weiter verarbeitet und gegebenenfalls als vollständiges Analysenprotokoll ausgedruckt werden zu können.Unsere prinzipielle Forderung für alle Verfahren war die völlige Unabhängigkeit der jeweiligen Endbestimmung von physikalischen Eichungen. Grundvoraussetzung war also eine strenge Linearität zwischen Menge und Meßwert. Diese schien uns am ehesten gewährleistet bei der Gasvolumetrie und der Titration.Über die von uns in der BASF entwickelten und eingesetzten Verfahren zur Schnellbestimmung der genannten Elemente wurde im einzelnen berichtet und auf neuere methodische und apparative Modifikationen hingewiesen. Ein Schwerpunkt sollte dabei die Möglichkeit der Automation der verschiedenen Analysenverfahren sein. Auch die notwendige Wirtschaftlichkeit in Relation zum Grad der Automation wurde diskutiert.

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Presented at the International Symposium on Microchemical Techniques 1977 at Davos, 22–27 May, 1977.     

Bestimmung der Kohlenstoffdreifachbindung durch quantitative selektive Hydrierung

Zusammenfassung CC-Dreifachbindungen können durch selektive Hydrierung bestimmt werden, wobei pro Dreifachbindung 1 Mol Wasserstoff aufgenommen wird. Die Hydrierung erfolgt am besten im Mikromaßstab. Sie wird in Wasser in Gegenwart eines mit Zn inaktivierten Pd/CaCO₃-Katalysators durchgeführt. Die Hydrierungsgeschwindigkeit kann durch Zusatz von Spuren basischer Stoffe wesentlich erhöht werden. Genügend stark aktivierte Doppelbindungen werden unter den Versuchsbedingungen ebenfalls hydriert und täuschen dann Kohlenstoff-Dreifachbindungen vor. — Der gleiche Katalysator hydriert Acetylenalkohole in Eisessig als Lösungsmittel ohne Angriff der OH-Gruppen zu entsprechenden gesätt. Alkoholen.

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Summary CC triple bonds are determined by selective hydrogenation; 1 triple bond adds 1 mol hydrogen. The hydrogenation is most successfully carried out in the micro scale in water as solvent. A Pd/CaCO₃ catalyst, inactivated by zinc, is used. The rate of hydrogenation is significantly increased by addition of traces of alcaline substances. Sufficiently activated olefinic double bonds add also hydrogen and simulate therefore CC triple bonds. — By use of acetic acid as solvent acetylenic alcohols add hydrogen in presence of the same catalyst forming the corresponding saturated alcohols without attacking the OH-group.

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Herrn Prof. Dr. A. Steinhofer zum 60. Geburtstag gewidmet.

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Wir danken Herrn Dr. Pasedach und Herrn Dr. Pfab für wertvolle Anregungen. Für die sorgfältige Durchführung der Versuche danken wir Herrn G. Nicklas, A. Schlindwein und H. Trarbach.     

The Amber biomolecular simulation programs

We describe the development, current features, and some directions for future development of the Amber package of computer programs. This package evolved from a program that was constructed in the late 1970s to do Assisted Model Building with Energy Refinement, and now contains a group of programs embodying a number of powerful tools of modern computational chemistry, focused on molecular dynamics and free energy calculations of proteins, nucleic acids, and carbohydrates.     

Conformational preferences for hydroxyl groups in substituted tetrahydropyrans

Quantum mechanical (ab initio and semiempirical) and force field calculations are reported for representative torsion potentials in several tetrahydropyran derivatives. The overall agreement between the various methods is quite good except that the AMBER torsion profiles are sensitive to the choice of atomic point charges. Using electrostatic potential (ESP) derived atomic point charges determined with the STO-3G basis set we find that AMBER is able to match the best quantum mechanical results quite well. However, when the point charges are derived using the 6-31G* basis set we find that scaling the intramolecular electrostatic nonbond interactions is necessary. AM1 does not work very well for these compounds when compared to the ab initio methods and, therefore, should only be used in cases when ab initio calculations would be prohibitive. Based upon our results we feel that any force field that makes use of 6-31G* ESP derived atomic point charges will need to scale intramolecular interactions. Implications of scaling intramolecular interactions to the development of force fields based on 6-31G* ESP derived atomic point charges are discussed. © 1992 by John Wiley & Sons, Inc.     

Atomic charges derived from semiempirical methods

It is demonstrated that semiempirical methods give electrostatic potential (ESP) derived atomic point charges that are in reasonable agreement with ab initio ESP charges. Furthermore, we find that MNDO ESP charges are superior to AM1 ESP charges in correlating with ESP charges derived from the 6-31G* basis set. Thus, it is possible to obtain 6-31G* quality point charges by simply scaling MNDO ESP charges. The charges are scaled in a linear (y = Mx) manner to conserve charge. In this way researchers desiring to carry out force field simulations or minimizations can obtain charges by using MNDO, which requires much less computer time than the corresponding 6-31G* calculation.     

Diazeniumdiolate ions as leaving groups in anomeric displacement reactions: a protection-deprotection strategy for ionic diazeniumdiolates

Diazeniumdiolate ions [R2N-N(O)=N-O-] are of growing interest pharmacologically for their ability to generate up to two molar equivalents of bioactive nitric oxide (NO) spontaneously on protonating the amino nitrogen. Accordingly, their stability increases as the pH is raised. Here we show that the corresponding beta-glucosides [R2N-N(O)=N-O-Glc] decreased in stability with pH; when R2N was diethylamino, the rate equation was kobs = ko + kOH- [OH-], where ko = 7.8 x 10-7 s-1 and kOH- = 5.3 x 10-3 M-1 s-1. The primary products were 1,6-anhydroglucose and the regenerated R2N-N(O)=N-O- ion. The results were qualitatively similar to those of beta-glucosyl fluoride and p-nitrophenoxide, whose hydrolyses have been rationalized as proceeding via a glycal oxide intermediate. This chemistry offers a convenient strategy for protecting heat- and acid-sensitive diazeniumdiolate ions during manipulations that would otherwise destroy them. As an example, a poly(urethane) film that generated NO in physiological buffer at a surface flux comparable to that of the mammalian vascular endothelium was prepared by glucosylating the ionic diazeniumdiolate group attached to the diol monomer before reacting it with the bis-isocyanate, then removing the saccharide with base when the protecting group was no longer needed.     

Lithiated Clusters from Primary Silylphosphanes and Silylarsanes: Spherical Bodies with and without Li2O Filling

Molecular clusters with archimedean and platonic shape , which in order to build a closed polyhedron, spontaneously eliminate H₂ or voluntarily encapsulate Li₂O as a “cluster nucleus”, result from the dilithiation of primary silylphosphanes and silylarsanes with BuLi. Thus, the first mixed-valent, decameric P₁₀Li₁₆ cluster 1 was obtained from iPr₃SiPH₂ and tBuLi (molar ratio 1:2) with strict exclusion of LiOH and Li₂O, whereas partial metalation in the presence of LiOH initially leads to a dodecameric, Li₂O-containing cluster 2 , from which the three-shell cluster 3 with a [Li₆O]⁴⁺ core is obtained.