Generate: a program for 3-D structure generation and conformational analysis of peptides and peptidomimetics

The program Generate, aimed at generating 3-D structures for peptides and peptidomimetics, is presented. The algorithm is based on a build-up procedure, using a library of conformations of amino acid residues. This library is built from conformational analysis of amino acids placed in a di- or tripeptide environment to mimic the surroundings of the amino acid in a true peptide, considering different positions of the residue in the peptide chain (peptidyl fragment, NH(+)(3)-terminus or COO(-)-terminus). Cis-trans isomerism in the amide bonds is taken into account by construction of rotamer libraries for different isomers. Water solvation is included through the GB/SA model. New amino acid residues can easily be added to the libraries, making it possible to generate conformations of peptidomimetics.     

Dynamic characterization of hysteresis elements in mechanical systems. I. Theoretical analysis

The pre-sliding-pre-rolling phase of friction behavior is dominated by rate-independent hysteresis. Many machine elements in common engineering use exhibit, therefore, the characteristic of "hysteresis springs," for small displacements at least. Plain and rolling element bearings that are widely used in motion guidance of machine tools are typical examples. While the presence of a hysteresis element may mark the character of the resulting dynamics, little is to be found about this topic in the literature. The study of the nonlinear dynamics caused by such elements becomes imperative if we wish to achieve accurate control of such machines. In this Part I of the investigation, we examine a single-degree-of-freedom mass-hysteresis-spring system and show that, while the free response case is amenable to an exact solution, the more important case of forced response has no closed form solution and requires other methods of treatment. We consider harmonic-balance analysis methods (which are common analysis tools in engineering) suitable for frequency-domain treatment, in particular the approximate describing function (DF) method, and compare those results with "exact" numerical simulations. The DF method yields basically a linear equation with amplitude-dependent modal parameters. We find that agreement in the frequency response function, between DF and exact solution, is good for small excitation amplitudes and for very large amplitudes. Intermediate values, however, show high sensitivity to amplitude variations and, consequently, no regular solution is obtainable by either approach. This appears to be an inherent property of the system pointing to the need for developing further analysis methods. Experimental verification of the analysis outlined in this Part I is given in Part II of the paper.     

Processive Catalysis

Nature’s enzymes are an ongoing source of inspiration for scientists. The complex processes behind their selectivity and efficiency is slowly being unraveled, and these findings have spawned many biomimetic catalysts. However, nearly all focus on the conversion of small molecular substrates. Nature itself is replete with inventive catalytic systems which modify, replicate, or decompose entire polymers, often in a processive fashion. Such processivity can, for example, enhance the rate of catalysis by clamping to the polymer substrate, which imparts a large effective molarity. Reviewed herein are the various strategies for processivity in nature’s arsenal and their properties. An overview of what has been achieved by chemists aiming to mimic one of nature’s greatest tricks is also included.     

Squeezing,Then Stacking: From Breathing Pores to Three‐Dimensional Ionic Self‐Assembly under Electrochemical Control

We demonstrate the spontaneous and reversible transition between the two‐ and three‐dimensional self‐assembly of a supramolecular system at the solid–liquid interface under electrochemical conditions, using in situ scanning tunneling microscopy. By tuning the interfacial potential, we can selectively organize our target molecules in an open porous pattern, fill these pores to form an auto‐host–guest structure, or stack the building blocks in a stratified bilayer. Using a simple electrostatic model, we rationalize which charge density is required to enable bilayer formation, and conversely, which molecular size/charge ratio is necessary in the design of new building blocks. Our results may lead to a new class of electrochemically controlled dynamic host–guest systems, artificial receptors, and smart materials.     

Probing Functional Heteromeric Chemokine Protein–Protein Interactions through Conformation‐Assisted Oxime Ligation

Protein–protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially involved in pathological disorders such as cancer, atherosclerosis, and HIV. It remains unclear whether this functional modulation is mediated by heterodimer formation or by the additive effects of mixed chemokines on their respective receptors. To address this issue, we report the synthesis of a covalent RANTES‐PF4 heterodimer (termed OPRAH) by total chemical synthesis and oxime ligation, with an acceleration of the final ligation step driven by PPIs between RANTES and PF4. Compared to mixed separate chemokines, OPRAH exhibited increased biological activity, thus providing evidence that physical formation of the heterodimer indeed mediates enhanced function.     

Development and validation of a simple thin layer chromatographic method for the analysis of artemisinin in Artemisia annua L. plant extracts

Owing to the development of parasite resistance to standard antimalarial treatments like chloroquine and sulfadoxine-pyrimethamine, the demand for Artemisia annua, a key ingredient for new and highly effective antimalarial drugs, is huge. Therefore selective and precise methods to determine the content of artemisinin in dry plant material and in raw impure extracts are needed. In this work a method is described for the clear separation and extraction of artemisinin from other plant components in the Artemisia annua L. plant by thin-layer chromatography (TLC). To obtain optimal extraction and recovery efficiency, several parameters were evaluated, including choice of extraction solvent, TLC plate type and sensitivity between UV and visible light. Method validation was performed on both the dry plant material and non-purified plant extracts. Toluene presented the highest extraction efficiency compared with petroleum ether, hexane and methanol. Reversed-phase plates showed more concentrated spots than normal-phase plates, while the sensitivity of the analysis in UV was comparable to that in visible light but less precise. The impure plant extracts were analyzed by both TLC and HPLC-UV at 215 nm and both methods met the requirements for linearity, selectivity, precision and accuracy. Hence, the proposed TLC method can easily be used for both qualitative and quantitative control of the raw plant extract in areas where advanced methods are scarce.     

A new colorimetric test for solid-phase amines and thiols

A new, efficient, sensitive, and reliable color test for the visual detection of resin-bound primary and secondary amines is described. The reaction between amines and 1-methyl-2-(4'-nitrophenyl)-imidazo[1,2- a]pyrimidinium perchlorate (DESC) provides the "on-bead generated" colored stable intermediate azadiene. The developed protocols allow detection of resin-bound primary amines in the presence of secondary amines. The test can also be used for the detection of resin bound thiols.