Effects of hydrogen bonding on amide-proton chemical shift anisotropy in a proline-containing model peptide

Longitudinal relaxation due to cross-correlation between dipolar ((HN-1H alpha)-H-1) and amide-proton chemical shift anisotropy (H-1(N) CSA) has been measured in a model tripeptide Piv-(L)Pro-(L)Pro-(L)Phe-OMe. The peptide bond across diproline segment is known to undergo cis/trans isomerization and only in the cis form does the lone Phe amide-proton become involved in intramolecular hydrogen bonding. The strength of the cross correlated relaxation interference is found to be significantly different between cis and trans forms, and this difference is shown as an influence of intramolecular hydrogen bonding on the amide-proton CSA. (C) 2015 Elsevier B.V. All rights reserved.

Dynamics of the chemical bond: inter- and intra-molecular hydrogen bond

In this discussion, we show that a static definition of a `bond' is not viable by looking at a few examples for both inter-and intra-molecular hydrogen bonding. This follows from our earlier work (Goswami and Arunan, Phys. Chem. Chem. Phys. 2009, 11, 8974) which showed a practical way to differentiate `hydrogen bonding' from `van der Waals interaction'. We report results from ab initio and atoms in molecules theoretical calculations for a series of Rg center dot center dot center dot HX complexes (Rg = He/Ne/Ar and X = F/Cl/Br) and ethane-1,2-diol. Results for the Rg center dot center dot center dot HX/DX complexes show that Rg center dot center dot center dot DX could have a `deuterium bond' even when Rg center dot center dot center dot HX is not `hydrogen bonded', according to the practical criterion given by Goswami and Arunan. Results for ethane-1,2-diol show that an `intra-molecular hydrogen bond' can appear during a normal mode vibration which is dominated by the O center dot center dot center dot O stretching, though a `bond' is not found in the equilibrium structure. This dynamical `bond' formation may nevertheless be important in ensuring the continuity of electron density across a molecule. In the former case, a vibration `breaks' an existing bond and in the later case, a vibration leads to `bond' formation. In both cases, the molecule/complex stays bound irrespective of what happens to this `hydrogen bond'. Both these cases push the borders on the recent IUPAC recommendation on hydrogen bonding (Arunan et al. Pure. Appl. Chem. 2011, 83 1637) and justify the inclusive nature of the definition.

Chemical-free graphene by unzipping carbon nanotubes using cryo-milling

Current paper reports synthesis of chemical free graphene by unzipping of the carbon nanotubes (CNTs) using high strain rate deformation at 150K. A specially designed cryomill operating at 150 K was used for the experiments. The mechanism of unzipping was further explored using molecular dynamics (MD) simulations. Both experimental and simulation results reveal two modes of unzipping through radial and shear loading. (C) 2015 Elsevier Ltd. All rights reserved.

Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical Library(TM) using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 mu M and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays. (C) 2015 Elsevier Ltd. All rights reserved.

Bolaamphiphiles as carriers for siRNA delivery: From chemical syntheses to practical applications

In this study we have investigated a new class of cationic lipids - ``bolaamphiphiles'' or ``bolas'' - for their ability to efficiently deliver small interfering RNAs (siRNAs) to cancer cells. The bolas of this study consist of a hydrophobic chain with one or more positively charged head groups at each end. Recently, we reported that micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Our previous studies validated that; bolaamphiphiles can be designed to vary the magnitude of siRNA shielding, its delivery, and its subsequent release. To further understand the structural features of bolas critical for siRNAs delivery, new structurally related bolas (GLH-58 and GLH-60) were designed and synthesized from jojoba oil. Both bolas have similar hydrophobic domains and contain either one, in GLH-58, or two, in GLH-60 positively charged head groups at each end of the hydrophobic core. We have computationally predicted and experimentally validated that GLH-58 formed more stable nano sized micelles than GLH-60 and performed significantly better in comparison to GLH-60 for siRNA delivery. GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5 mu g/mL, well below the toxic dose. Moreover, delivery of multiple different siRNAs targeting the HIV genome demonstrated further inhibition of virus production. Published by Elsevier B.V.

Dissecting Ubiquitin Folding Using the Self-Organized Polymer Model

Folding of Ubiquitin (Ub), a functionally important protein found in eukaryotic organisms, is investigated at low and neutral pH at different temperatures using simulations of the coarse-grained self-organized-polymer model with side chains (SOP-SC). The melting temperatures (T-m's), identified with the peaks in the heat capacity curves, decrease as pH decreases, in qualitative agreement with experiments. The calculated radius of gyration, showing dramatic variations with pH, is in excellent agreement with scattering experiments. At T-m Ub folds in a two-state manner at low and neutral pH. Clustering analysis of the conformations sampled in equilibrium folding trajectories at T-m with multiple transitions between the folded and unfolded states, shows a network of metastable states connecting the native and unfolded states. At low and neutral pH, Ub folds with high probability through a preferred set of conformations resulting in a pH-dependent dominant folding pathway. Folding kinetics reveal that Ub assembly at low pH occurs by multiple pathways involving a combination of nucleation-collapse and diffusion collision mechanism. The mechanism by which Ub folds is dictated by the stability of the key secondary structural elements responsible for establishing long-range contacts and collapse of Ub. Nucleation collapse mechanism holds if the stability of these elements are marginal, as would be the case at elevated temperatures. If the lifetimes associated with these structured microdomains are on the order of hundreds of microseconds, then Ub folding follows the diffusion collision mechanism with intermediates, many of which coincide with those found in equilibrium. Folding at neutral pH is a sequential process with a populated intermediate resembling that sampled at equilibrium. The transition state structures, obtained using a P-fold analysis, are homogeneous and globular with most of the secondary and tertiary structures being native-like. Many of our findings for both the thermodynamics and kinetics of folding are not only in agreement with experiments but also provide missing details not resolvable in standard experiments. The key prediction that folding mechanism varies dramatically with pH is amenable to experimental tests.

Atmospheric pressure plasma chemical vapor deposition reactor for 100 mm wafers, optimized for minimum contamination at low gas flow rates

Gas discharge plasmas used for thinfilm deposition by plasma-enhanced chemical vapor deposition (PECVD) must be devoid of contaminants, like dust or active species which disturb the intended chemical reaction. In atmospheric pressure plasma systems employing an inert gas, the main source of such contamination is the residual air inside the system. To enable the construction of an atmospheric pressure plasma (APP) system with minimal contamination, we have carried out fluid dynamic simulation of the APP chamber into which an inert gas is injected at different mass flow rates. On the basis of the simulation results, we have designed and built a simple, scaled APP system, which is capable of holding a 100 mm substrate wafer, so that the presence of air (contamination) in the APP chamber is minimized with as low a flow rate of argon as possible. This is examined systematically by examining optical emission from the plasma as a function of inert gas flow rate. It is found that optical emission from the plasma shows the presence of atmospheric air, if the inlet argon flow rate is lowered below 300 sccm. That there is minimal contamination of the APP reactor built here, was verified by conducting an atmospheric pressure PECVD process under acetylene flow, combined with argon flow at 100 sccm and 500 sccm. The deposition of a polymer coating is confirmed by infrared spectroscopy. X-ray photoelectron spectroscopy shows that the polymer coating contains only 5% of oxygen, which is comparable to the oxygen content in polymer deposits obtained in low-pressure PECVD systems. (C) 2015 AIP Publishing LLC.

Common effect of chemical and external pressures on the magnetic properties of RCoPO (R = La, Pr, Nd, Sm). II.

We investigate the direct correspondence between Co band ferromagnetism and structural parameters in the pnictide oxides RCoPO for different rare-earth ions (R = La, Pr, Nd, Sm) by means of muon-spin spectroscopy and ab initio calculations, complementing our results published previously G. Prando et al., Common effect of chemical and external pressures on the magnetic properties of RCoPO (R = La, Pr), Phys. Rev. B 87, 064401 (2013)]. We find that both the transition temperature to the ferromagnetic phase T-C and the volume of the crystallographic unit cell V are conveniently tuned by the R ionic radius and/or external pressure. We report a linear correlation between T-C and V and our ab initio calculations unambiguously demonstrate a full equivalence of chemical and external pressures. As such, we show that R ions influence the ferromagnetic phase only via the induced structural shrinkage without involving any active role from the electronic f degrees of freedom, which are only giving a sizable magnetic contribution at much lower temperatures.

Synthesis of 3-dimensional porous graphene nanosheets using electron cyclotron resonance plasma enhanced chemical vapour deposition

Microwave plasma driven chemical vapour deposition was used to synthesize graphene nanosheets from a mixture of acetylene and hydrogen gas molecules. In this plasma, acetylene decomposes to carbon atoms that form nanostructures in the outlet plasma stream and get deposited on the substrate. The GNS consists of a few layers of graphene aligned vertically to the substrate. Graphene layers have been confirmed by high-resolution transmission electron microscopy, and Raman spectral studies were conducted to observe the defective nature of the sample. The growth of nanosheets in a vertical direction is assumed to be due to the effect of electric field and from the difference in the deposition rate in the axial and parallel directions. These vertical graphene sheets are attractive for various applications in energy storage and sensors.

Interplay of Substrate Conductivity, Cellular Microenvironment, and Pulsatile Electrical Stimulation toward Osteogenesis of Human Mesenchymal Stem Cells in Vitro

The influences of physical stimuli such as surface elasticity, topography, and chemistry over mesenchymal stem cell proliferation and differentiation are well investigated. In this context, a fundamentally different approach was adopted, and we have demonstrated the interplay of inherent substrate conductivity, defined chemical composition of cellular microenvironment, and intermittent delivery of electric pulses to drive mesenchymal stem cell differentiation toward osteogenesis. For this, conducting polyaniline (PANI) substrates were coated with collagen type 1 (Coll) alone or in association with sulfated hyaluronan (sHya) to form artificial extracellular matrix (aECM), which mimics the native microenvironment of bone tissue. Further, bone marrow derived human mesenchymal stem cells (hMSCs) were cultured on these moderately conductive (10(-4)10(-3) S/cm) aECM coated PANI substrates and exposed intermittently to pulsed electric field (PEF) generated through transformer-like coupling (TLC) approach over 28 days. On the basis of critical analysis over an array of end points, it was inferred that Coll/sHya coated PANI (PANI/Coll/sHya) substrates had enhanced proliferative capacity of hMSCs up to 28 days in culture, even in the absence of PEF stimulation. On the contrary, the adopted PEF stimulation protocol (7 ms rectangular pulses, 3.6 mV/cm, 10 Hz) is shown to enhance osteogenic differentiation potential of hMSCs. Additionally, PEF stimulated hMSCs had also displayed different morphological characteristics as their nonstimulated counterparts. Concomitantly, earlier onset of ALP activity was also observed on PANI/Coll/sHya substrates and resulted in more calcium deposition. Moreover, real-time polymerase chain reaction results indicated higher mRNA levels of alkaline phosphatase and osteocalcin, whereas the expression of other osteogenic markers such as Runt-related transcription factor 2, Col1A, and osteopontin exhibited a dynamic pattern similar to control cells that are cultured in osteogenic medium. Taken together, our experimental results illustrate the interplay of multiple parameters such as substrate conductivity, electric field stimulation, and aECM coating on the modulation of hMSC proliferation and differentiation in vitro.

Multivariate PLS Modeling of Apicomplexan FabD-Ligand Interaction Space for Mapping Target-Specific Chemical Space and Pharmacophore Fingerprints

Biomolecular recognition underlying drug-target interactions is determined by both binding affinity and specificity. Whilst, quantification of binding efficacy is possible, determining specificity remains a challenge, as it requires affinity data for multiple targets with the same ligand dataset. Thus, understanding the interaction space by mapping the target space to model its complementary chemical space through computational techniques are desirable. In this study, active site architecture of FabD drug target in two apicomplexan parasites viz. Plasmodium falciparum (PfFabD) and Toxoplasma gondii (TgFabD) is explored, followed by consensus docking calculations and identification of fifteen best hit compounds, most of which are found to be derivatives of natural products. Subsequently, machine learning techniques were applied on molecular descriptors of six FabD homologs and sixty ligands to induce distinct multivariate partial-least square models. The biological space of FabD mapped by the various chemical entities explain their interaction space in general. It also highlights the selective variations in FabD of apicomplexan parasites with that of the host. Furthermore, chemometric models revealed the principal chemical scaffolds in PfFabD and TgFabD as pyrrolidines and imidazoles, respectively, which render target specificity and improve binding affinity in combination with other functional descriptors conducive for the design and optimization of the leads.