Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes

Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state (13)C, (15)N, and (31)P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors.     

Efficient and mild microwave-assisted stepwise functionalization of naphthalenediimide with alpha-amino acids

Microwave dielectric heating proved to be an efficient method for the one-pot and stepwise syntheses of symmetrical and unsymmetrical naphthalenediimide derivatives of alpha-amino acids. Acid-labile side chain protecting groups are stable under the reaction conditions; protection of the alpha-carboxylic group is not required. The stepwise condensation of different amino acids resulted in high yields of unsymmetrical naphthalenediimides. The reaction proceeds without racemization and is essentially quantitative.     

Thermodynamics of supramolecular naphthalenediimide nanotube formation: the influence of solvents, side chains, and guest templates

Amino-acid functionalized naphthalenediimides self-assemble into hydrogen-bonded supramolecular helical nanotubes via a noncooperative, isodesmic process; the self-assembly of ordered helical systems is usually realized through a cooperative process. This unexpected behavior was rationalized as a manifestation of entropy-enthalpy compensation. Fundamental insights into the thermodynamics governing this self-assembly were obtained through the fitting of the isodesmic model to (1)H NMR spectrometry and circular dichroism spectroscopy measurements. Furthermore, we have extended the application of this mathematical model, for the first time, to quantitatively estimate the effect of guests, solvents, and side chains on the stability of the supramolecular nanotube; most significantly, we demonstrate that C(60) acts as a template to stabilize the nanotube assembly and thereby substantially increase the degree of polymerization.     

A pilot study for the intrinsic labeling of egg proteins with 15N and 13C

The aim of this study was to produce intrinsically and uniformly doubly (15)N-(13)C-labeled proteins. These proteins can be used as intrinsic tracers of dietary amino acids, both α-amino groups and carbon skeletons, during postprandial metabolic utilization. Two (Rhodes) laying hens were fed for 16 days with a standard poultry diet supplemented with 0, 0.2% or 0.4% of a mixture of 20 doubly (15)N-(13)C-labeled AAs. A third hen was given a non-enriched diet, as the control. The eggs laid were collected over 24 days, from 3 days before to 4 days after supplementation. The (15)N and (13)C enrichments in proteins from white and yolk were measured by EA-IRMS and GC-C-IRMS for enrichment in individual amino acids. After 10 days of supplementation, the (15)N enrichment reached an isotopic plateau at 1500 to 3000 ‰, depending on the supplementation level, in both white and yolk while the (13)C enrichment was 220 to 650 ‰ in white and was 100 to 250 ‰ in yolk. The (15)N enrichment was similar among the amino acids, except for the aromatic ones in which the enrichment was lower. The δ(13)C values were variable among amino acids in both white and yolk, ranging from 77 ‰ for tyrosine to 555 ‰ for proline with the 0.2 % supplementation level. In conclusion, the incorporation of 0.2 % labeled amino acids in the hen diet allowed us to achieve sufficient enrichment for metabolic studies. However, due to the non-homogeneity of the (13)C labeling, adequate (13)C enrichment of individual amino acids must be considered depending on the investigated metabolic pathway.     

Coherent phonon dynamics in short-period InAs/GaSb superlattices

We have performed ultrafast pump-probe spectroscopy studies on a series of InAs/GaSb-based short-period superlattice (SL) samples with periods ranging from 46 Å to 71 Å. We observe two types of oscillations in the differential reflectivity with fast (∼$\sim$1–2 ps) and slow (∼$\sim$24 ps) periods. The period of the fast oscillations changes with the SL period and can be explained as coherent acoustic phonons generated from carriers photoexcited within the SL. This mode provides an alternative method for determining the SL period. The period of the slow mode depends on the wavelength of the probe pulse and can be understood as a propagating coherent phonon wavepacket modulating the reflectivity of the probe pulse as it travels from the surface into the sample.     

Low-loss surface modes and lossy hybrid modes in metamaterial waveguides

We show that waveguides with a dielectric core and a lossy metamaterial cladding (metamaterial-dielectric guides) can support hybrid ordinary-surface modes previously only known for metal-dielectric waveguides. These hybrid modes are potentially useful for frequency filtering applications as sharp changes in field attenuation occur at tailorable frequencies. Our results also show that the surface modes of a metamaterial-dielectric waveguide with comparable electric and magnetic losses can be less lossy than the surface modes of an analogous metal-dielectric waveguide with electric losses alone. Through a characterization of both slab and cylindrical metamaterial-dielectric guides, we find that the surface modes of the cylindrical guides show promise as candidates for all-optical control of low-intensity pulses.