Conformational sampling with Poisson–Boltzmann forces and a stochastic dynamics/Monte Carlo method: Application to alanine dipeptide

We apply a combination of stochastic dynamics and Monte Carlo methods (MC/SD) to alanine dipeptide, with solvation forces derived from a Poisson–Boltzmann model supplemented with apolar terms. Our purpose is to study the effects of the model parameters, such as the friction constant and the size of the electrostatic finite difference grid, on the rate of conformational sampling and on the accuracy of the resulting free energy map. For dialanine, a converged Ramachandran map is produced in significantly less time than what is required by stochastic dynamics or Monte Carlo alone. MC/SD is also shown to be faster, per timestep, than explicit methods. © 1997 John Wiley & Sons, Inc. J Comput Chem 18 : 1750–1759, 1997     

Covering models and optimization techniques for emergency response facility location and planning: a review

With emergencies being, unfortunately, part of our lives, it is crucial to efficiently plan and allocate emergency response facilities that deliver effective and timely relief to people most in need. Emergency Medical Services (EMS) allocation problems deal with locating EMS facilities among potential sites to provide efficient and effective services over a wide area with spatially distributed demands. It is often problematic due to the intrinsic complexity of these problems. This paper reviews covering models and optimization techniques for emergency response facility location and planning in the literature from the past few decades, while emphasizing recent developments. We introduce several typical covering models and their extensions ordered from simple to complex, including Location Set Covering Problem (LSCP), Maximal Covering Location Problem (MCLP), Double Standard Model (DSM), Maximum Expected Covering Location Problem (MEXCLP), and Maximum Availability Location Problem (MALP) models. In addition, recent developments on hypercube queuing models, dynamic allocation models, gradual covering models, and cooperative covering models are also presented in this paper. The corresponding optimization techniques to solve these models, including heuristic algorithms, simulation, and exact methods, are summarized.     

Application of 1‐methyl imidazole‐based ionic liquid‐stabilized silica‐coated Fe3O4 as a novel modified magnetic nanocatalyst for the synthesis of pyrano[2,3‐d]pyrimidines

1‐Methyl imidazole‐based ionic liquid‐stabilized silica‐coated Fe₃O₄ magnetic nanoparticles [Fe₃O₄@SiO₂@(CH₂)₃‐1‐methyl imidazole]HSO₄ as a solid acid magnetic nanocatalyst was explored in the synthesis of pyrano[2,3‐d]pyrimidine derivatives. Pyrano[2,3‐d]pyrimidine derivatives were synthesized by a highly efficient three‐component reaction of various benzaldehydes, malononitrile, and barbituric acid. The catalyst was characterized by using various analysis techniques such as Fourier transform infrared (FT‐IR) spectroscopy, X‐ray diffraction (XRD), differential scanning calorimetry‐thermogravimetry analysis (DSC‐TGA), scanning electron microscopy (SEM), and vibrating sample magnetometry (VSM).     

Deciphering common failures in molecular docking of ligand-protein complexes

Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as `soft' and `hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations.     

Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency

Antimicrobial alpha-helical alpha-peptides are part of the host-defense mechanism of multicellular organisms and could find therapeutic use against bacteria that are resistant to conventional antibiotics. Recent work from Hamuro et al. has shown that oligomers of beta-amino acids ("beta-peptides") that can adopt an amphiphilic helix defined by 14-membered ring hydrogen bonds ("14-helix") are active against Escherichia coli [Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200-12201]. We have created two series of cationic 9- and 10-residue amphiphilic beta-peptides to probe the effect of 14-helix stability on antimicrobial and hemolytic activity. 14-Helix stability within these series is modulated by varying the proportions of rigid trans-2-aminocyclohexanecarboxylic acid (ACHC) residues and flexible acyclic residues. We have previously shown that a high proportion of ACHC residues in short beta-peptides encourages 14-helical structure in aqueous solution [Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309-2310]. Circular dichroism of the beta-peptides described here reveals a broad range of 14-helix population in aqueous buffer, but this variation in helical propensity does not lead to significant changes in antibiotic activity against a set of four bacteria. Several of the 9-mers display antibiotic activity comparable to that of a synthetic magainin derivative. Among these 9-mers, hemolytic activity increases slightly with increasing 14-helical propensity, but all of the 9-mers are less hemolytic than the magainin derivative. Previous studies with conventional peptides (alpha-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because alpha-helix stability can be varied to only a limited extent among linear alpha-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with beta-peptides. For example, it is very rare for a linear alpha-peptide to display significant alpha-helix formation in aqueous solution and manifest antibacterial activity, while the linear beta-peptides described here range from fully unfolded to very highly folded in aqueous solution. This study shows that beta-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.     

Distinctive circular dichroism signature for 14-helix-bundle formation by beta-peptides

We identify a distinctive circular dichroism (CD) signature for self-assembled 14-helical beta-peptides. Our data show that self-assembly leads to a mimimum at 205 nm, which is distinct from the well-known minimum at 214 nm for a monomeric 14-helix. The onset of assembly is indicated by [theta]205/[theta]214>0.7. Our results will facilitate rapid screening for self-assembling beta-peptides and raise the possibility that far-UV CD will be useful for detecting higher-order structure for other well-folded oligoamide backbones.     

Epigenetic Modifiers Affect the Bioactive Compounds Secreted by an Endophyte of the Tropical Plant Piper longum

Seven endophytic fungi were isolated from the tropical medicinal plant Piper longum L. After preliminary screening, Phomopsis heveicola was selected for the epigenetic activation treatments. The antibacterial, antifungal, and antioxidant potentials of crude extracts obtained from the treatments (with and without epigenetic modifiers) were analyzed in vitro. The extracts inhibited growth of the human pathogens Pseudomonas aeruginosa, Shigella sonnei, Streptococcus pyogenes, and Salmonella typhi, as well as the phytopathogens Puccinia recondita, Rhizoctonia solani, Phytophthora infestans, and Botrytis cinerea. Furthermore, DPPH-scavenging activity was higher in valproic acid treated extracts. Volatile chemicals with known biological activities (measured with GC-MS/MS), were released in the valproic acid treatment. The antimicrobial potentials of the extracts were confirmed using MRM/MS analysis. The experiments revealed a new promising endophytic fungus, P. heveicola, to be utilized in biological plant protection and in biomedical applications.     

Rapid Isocratic HPLC Method and Sample Extraction Procedures for Measuring Carotenoid,Retinoid, and Tocopherol Concentrations in Human Blood and Breast Milk for Intervention Studies

Vitamin A deficiency continues to be a major public health concern in the developing world effecting over 200 million people. Interventions including carotenoid-rich fruits and vegetables, containing α- and β-carotene, and β-cryptoxanthin, are being tested for their potential to alleviate vitamin A deficiency in several countries. Thus, there is a need for a faster isocratic reverse-phase high pressure liquid chromatography (HPLC) method than the methods currently available. Efficient extraction procedures for biological samples are also valuable to save time, materials, and cost. We developed an HPLC method and compared several extraction methods for carotenoids, retinoids, and vitamin E in plasma and human breast milk. The method uses an Agilent 1100 system equipped with a Waters Spherisorb ODS2 column (3 × 125 mm 3 μm) and similar guard column (ThermoScientific ODS2 3 × 20 mm 3 μm). Mobile phase of 7:2:1 acetonitrile:dichloromethane:methanol was run at 0.5 mL min⁻¹, and run times were complete in approximately 8 min. This rapid method uses little solvent and provides excellent results in the analysis of these fat-soluble nutrients. Analyte measurements were repeatable using standards and plasma and were accurate compared to NIST certified and reference serum values. The validated HPLC method was applied to the analysis of plasma samples from a vitamin A intervention study.

     

Effects of tritiated water on the DNA of plasmid pBR 322

In an attempt to shed light on the influence of tritiated water for DNA we have investigated the damage with a simple plasmid DNA, pBR 322. The survival of covalently closed circular (CCC DNA) form was directly followed by agarose of gel electrophoresis. It was found that the survival percentage of DNA in tritiated water was observed almost the same as the irradiation of X-rays at the same absorbed doses. For the irradiation of gamma-rays, on the other hand, the decay rate was larger than those of both tritiated water and X-rays. The yields percentage of the broken pieces of DNA in tritiated water, X-rays and gamma-rays were found to be 43, 38 and 33% at 10(4) rad of the absorbed dose. It may be considered that the degree of danger in tritiated water is quite larger than of gamma-rays. It was also found that the dose rate effect was not observed in the case of tritiated water, X-rays and gamma-rays irradiation.