Drug–protein interaction with Vpu from HIV-1: proposing binding sites for amiloride and one of its derivatives

Vpu is an 81-amino-acid auxiliary protein of the genome of HIV-1. It is proposed that one of its roles is to enhance particle release by self-assembling to form water-filled channels enabling the flux of ions at the site of the plasma membrane of the infected cell. Hexamethylene amiloride has been shown to block Vpu channel activity when the protein is reconstituted into lipid bilayers. In a docking approach with monomeric, pentameric and hexameric bundle models of Vpu corresponding to the transmembrane part of the protein, a putative binding site of hexamethylene amiloride is proposed and is compared with the site for the nonpotent amiloride. The binding mode for both ligands is achieved by optimizing hydrogen bond interactions with serines. Binding energies and binding constants are the lowest for protonated hexamethylene amiloride in the pentameric bundle. Figure The proposed binding site of the Vpu channel blocker hexamethylene amiloride within the lumen of the Vpu bundle. The bundle is a homo-pentamer with each monomer consisting of the first 32 amino acids of Vpu including the transmembrane part of the protein which is encoded by HIV-1. The bundle atoms are shown in their van der Waals representation and the helix backbone in a ribbon representation. Residues Trp-23 and Ser-24 are highlighted as sticks. Hexamethylene amiloride is shown in yellow (C atoms) and blue (N atoms)     

The effect of silane incorporation on a metal adhesive interface: A study by electron energy loss spectroscopy

A silane-based adhesive formulation, used in the aerospace industry, was studied using sub-nanometre spatially resolved energy loss spectroscopy, as a function of the concentration of silane used in the adhesive. The changes in the relative oxygen concentration and the occupancy of p-type states in the oxygen density of states reveal the existence of a composite layer between the aluminium and the epoxy resin. This composite layer is prevalent in the 1% (w/w) organosilane sample, whilst it is smaller or absent for the 0.5% and 2% (w/w) silane concentration. These observations correlate well with the observed macroscopic durabilities observed when these adhesives are used for the structural adhesive bonding of aluminium aerospace alloys.     

Effects of low-frequency biasing on spontaneous otoacoustic emissions: amplitude modulation

The dynamic effects of low-frequency biasing on spontaneous otoacoustic emissions (SOAEs) were studied in human subjects under various signal conditions. Results showed a combined suppression and modulation of the SOAE amplitudes at high bias tone levels. Ear-canal acoustic spectra demonstrated a reduction in SOAE amplitude and growths of sidebands while increasing the bias tone level. These effects varied depending on the relative strength of the bias tone to a particular SOAE. The SOAE magnitudes were suppressed when the cochlear partition was biased in both directions. This quasi-static modulation pattern showed a shape consistent with the first derivative of a sigmoid-shaped nonlinear function. In the time domain, the SOAE amplitudes were modulated with the instantaneous phase of the bias tone. For each biasing cycle, the SOAE envelope showed two peaks each corresponded to a zero crossing of the bias tone. The temporal modulation patterns varied systematically with the level and frequency of the bias tone. These dynamic behaviors of the SOAEs are consistent with the shifting of the operating point along the nonlinear transducer function of the cochlea. The results suggest that the nonlinearity in cochlear hair cell transduction may be involved in the generation of SOAEs.     

Development of an automated in situ fracture stage for a ToF‐SIMS system

The design philosophy and implementation of an ultra high vacuum (UHV), PC controlled, automated in situ fracture stage for a surface analysis system is described. ToF‐SIMS spectra are shown to illustrate the improvement in spectral quality obtained from micro‐compact tension (CT) tests of polymer matrix fracture surfaces produced using the fracture stage in UHV compared to those obtained from a sample tested at air. This system is flexible in that by changing the capacity of the load cell it is possible to reduce or increase maximum loads as the specimen type and material demands. The stage has been designed with instrumental flexibility in mind, utilising commercial SEM‐stub type sample mounts, and can thus be used for AES/SAM and XPS investigations, as well as ToF‐SIMS analysis, in the authors' laboratory. Copyright © 2008 John Wiley & Sons, Ltd.     

Coupled-cluster study of isomers of H2SO2

A theoretical study has been made on six isomers of H2SO2 using coupled-cluster singles and doubles with noniterative triple excitations (CCSD(T)). The isomers studied are sulfoxylic acid (S(OH)2; C2 and Cs conformers), sulfinic acid (HS(=O)OH; 2 C1 conformers), dihydrogen sulfone (H2SO2; C2v), sulfhydryl hydroperoxide (HSOOH; C1), thiadioxirane (Cs), and dihydrogen persulfoxide (H2SOO; Cs). Molecular geometries, harmonic vibrational frequencies, and infrared intensities of all species were obtained using the CCSD(T) method and the 6-311++G(2d,2p) basis set. All aforementioned species were found to be local minima, with the exception of thiadioxirane, which has one imaginary frequency. A prior possible infrared observation of sulfinic acid was reassessed on the basis of the present data. In agreement with previous MP2 results, the present CCSD(T) data provide support for at most 4 of the 8 observed frequencies. The CCSD(T) frequencies and intensities should be of assistance in future identification of H2SO2 isomers by vibrational spectroscopy. Relative energies were calculated using the CCSD(T) method and several larger basis sets. As found previously, the lowest energy species is C2 S(OH)2, followed by Cs S(OH)2, HS(=O)OH, H2SO2, HSOOH, thiadioxirane, and H2SOO. Expanding the basis set significantly reduces the relative energies of HS(=O)OH and H2SO2. The CCSD(T) method was used with extended basis sets (up to aug-cc-pV(Q+d)Z) and basis set extrapolation in two reaction schemes to calculate the DeltaH degrees t (25 degrees C) of C2 S(OH)2. The two reaction schemes gave -285.8 and -282.7 kJ mol-1, which are quite close to a prior theoretical estimate (-290 kJ mol-1).     

Interaction of metal porphyrins with fullerene C60: a new insight

The electronic structure and bonding in the noncovalent, supramolecular complexes of fullerene C60 with a series of first-row transition metal porphines MP (M=Fe, Co, Ni, Cu, Zn) have been re-examined with DFT methods. A dispersion correction was made for the C60-MP binding energy through an empirical method (J. Comput. Chem. 2004, 25, 1463). Several density functionals and two types of basis sets were employed in the calculations. Our calculated results are rather different from those obtained in a recent paper (J. Phys. Chem. A 2005, 109, 3704). The ground state of C60.FeP is predicted to be high spin (S=2); the low-spin (S=0), closed-shell state is even higher in energy than the intermediate-spin (S=1) state. With only one electron in the Co-dz2 orbital, the calculated Co-C60 distance is in fact rather short, about 0.1 A longer than the Fe-C60 distance in high-spin C60.FeP. Double occupation of an M-dz2 orbital in MP prevents close association of any axial ligand, and so the Ni-C60, Cu-C60, and Zn-C60 distances are much longer than the Co-C60 one. The evaluated MP-C60 binding energies (Ebind) are 0.8 eV (18.5 kcal/mol) for M=Fe/Co and 0.5 eV (11.5 kcal/mol) for M=Ni/Cu/Zn (Ebind is about 0.2 eV larger in the case of C60-MTPP). They are believed to be reliable and accurate based on our dispersion-corrected DFT calculations that included the counterpoise (CP) correction. The effects of the C60 contact on the redox properties of MP were also examined.