Changes In Charge Distribution Research Articles

Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport

The cholesterol storage disorder Niemann-Pick type C (NPC) disease is caused by defects in either of two late endosomal/lysosomal proteins, NPC1 and NPC2. NPC2 is a 16-kDa soluble protein that binds cholesterol in a 1:1 stoichiometry and can transfer cholesterol between membranes by a mechanism that involves protein-membrane interactions. To examine the structural basis of NPC2 function in cholesterol trafficking, a series of point mutations were generated across the surface of the protein. Several NPC2 mutants exhibited deficient sterol transport properties in a set of fluorescence-based assays. Notably, these mutants were also unable to promote egress of accumulated intracellular cholesterol from npc2(-/-) fibroblasts. The mutations mapped to several regions on the protein surface, suggesting that NPC2 can bind to more than one membrane simultaneously. Indeed, we have previously demonstrated that WT NPC2 promotes vesicle-vesicle interactions. These interactions were abrogated, however, by mutations causing defective sterol transfer properties. Molecular modeling shows that NPC2 is highly plastic, with several intense positively charged regions across the surface that could interact favorably with negatively charged membrane phospholipids. The point mutations generated in this study caused changes in NPC2 surface charge distribution with minimal conformational changes. The plasticity, coupled with membrane flexibility, probably allows for multiple cholesterol transfer routes. Thus, we hypothesize that, in part, NPC2 rapidly traffics cholesterol between closely appositioned membranes within the multilamellar interior of late endosomal/lysosomal proteins, ultimately effecting cholesterol egress from this compartment.

Re-creation of aerosol charge state found near HV power lines using a high voltage corona charger

Corona ionisation from AC HV power lines (HVPL) can release ions into the environment, which have the potential to electrically charge pollutant aerosol in the atmosphere. It has been hypothesised that these charged particles have an enhanced probability of being deposited in human airways upon inhalation due to electrostatic attraction by image charge within the lung, with implications for human health. Carbonaceous aerosol particles from a Technegas generator were artificially charge-enhanced using a corona charger. Once generated, particles were passed through the charger, which was either on or off, and stored in a 15 litre conducting bag for ∼20 minutes to observe size and charge distribution changes over time. Charge states were estimated using two Sequential Mobility Particle Sizers measuring the size and mobility distributions. Charge-neutral particles were measured 7 times and positive particles 9 times, the average charge-neutral value of x was 1.00 (sd = 0.06) while the average positive value was 4.60 (0.72). The system will be used to generate positive or charge neutral particles for delivery to human volunteers in an inhalation study to assess the impact of charge on ultrafine (size < 100 nm) particle deposition.

Proline-15 creates an amphipathic wedge in maculatin 1.1 peptides that drives lipid membrane disruption

The membrane interaction of peptides derived from maculatin 1.1 and caerin 1.1, with the sequence motif of N and C termini of maculatin 1.1, was compared in order to understand the role of these common sequence motifs, which encompass critical proline residues, on peptide secondary structure and on membrane binding and disruption in zwitterionic and anionic membranes. The peptides incorporated a single substitution with lysine or deletion of the central region to mimic the length of the antimicrobial peptides, citropin 1.1 and aurein 1.2. The impact of these changes in the sequence, length and physicochemical properties, on lytic activity and structure was assessed by dye-release from lipid vesicles and the change in the bilayer order as a function of membrane-bound peptide mass. All peptides adopted similar degrees of helical structure in both membrane systems. In addition, all peptide analogues were less active than either maculatin 1.1 or caerin 1.1 in dye release assays. The membrane binding was analyzed by dual polarization interferometry and the results showed that membrane binding was significantly affected by changes in the hydrophobic environment of Pro-15. Moreover, changes in the relative distribution of charge and hydrophobicity flanking Pro-15 also caused significant changes to the membrane order. Overall, the proline residue plays an important role in inducing a peptide structure that enhances the activity of these antimicrobial peptides.

ChemInform Abstract: Gated Supramolecular Chemistry in Hybrid Mesoporous Silica Nanoarchitectures: Controlled Delivery and Molecular Transport in Response to Chemical, Physical and Biological Stimuli

AbstractReview: [184 refs.

Electronic structural basis for the atomic partial charges of planar molecular systems derived from out-of-plane dipole derivatives.

The method of deriving atomic partial charges from out-of-plane dipole derivatives has gained renewed interest as a useful method for identifying the changes in charge distribution upon molecular motion. To understand the nature of those atomic partial charges and to explore possible wide applicability of this method, the modulations in the electron density induced by out-of-plane atomic displacements are analyzed by calculating two-dimensional electronic polarization derivatives. It is shown that their amplitudes are substantially delocalized to the spatial regions of the adjacent atoms, suggesting the size of the planar region required for applying this method to locally planar systems, such as the peptide group capped by alkyl groups. It is also shown that, in molecular complexes, the amplitudes of electronic polarization derivatives are affected rather strongly by the polarization effect, indicating the way to use this method to estimate the extent of intermolecular charge transfer in hydrogen-bonded systems.

Observation of structural relaxation during exciton self-trapping via excited-state resonant impulsive stimulated Raman spectroscopy.

We detect the change in vibrational frequency associated with the transition from a delocalized to a localized electronic state using femtosecond vibrational wavepacket techniques. The experiments are carried out in the mixed-valence linear chain material [Pt(en)2][Pt(en)2Cl2]⋅(ClO4)4 (en = ethylenediamine, C2H8N2), a quasi-one-dimensional system with strong electron-phonon coupling. Vibrational spectroscopy of the equilibrated self-trapped exciton is carried out using a multiple pulse excitation technique: an initial pump pulse creates a population of delocalized excitons that self-trap and equilibrate, and a time-delayed second pump pulse tuned to the red-shifted absorption band of the self-trapped exciton impulsively excites vibrational wavepacket oscillations at the characteristic vibrational frequencies of the equilibrated self-trapped exciton state by the resonant impulsive stimulated Raman mechanism, acting on the excited state. The measurements yield oscillations at a frequency of 160 cm(-1) corresponding to a Raman-active mode of the equilibrated self-trapped exciton with Pt-Cl stretching character. The 160 cm(-1) frequency is shifted from the previously observed wavepacket frequency of 185 cm(-1) associated with the initially generated exciton and from the 312 cm(-1) Raman-active symmetric stretching mode of the ground electronic state. We relate the frequency shifts to the changes in charge distribution and local structure that create the potential that stabilizes the self-trapped state.

Molecular basis of E. colil-threonine aldolase catalytic inactivation at low pH

l-Threonine aldolases (TAs), a family of enzymes belonging to the fold-type I pyridoxal 5′-phosphate (PLP) dependent enzymes, play a role in catalyzing the reversible cleavage of l-3-hydroxy-α-amino acids to glycine and the corresponding aldehydes. Threonine aldolases have great biotechnological potential for the syntheses of pharmaceutically relevant drug molecules because of their stereospecificity. The pH-dependency of their catalytic activity, affecting reaction intermediates, led us to study the effect of low-pH on Escherichia coli TA (eTA) structure. We report here a low-pH crystal structure of eTA at 2.1Å resolution, with a non-covalently bound uncleaved l-serine substrate, and a PLP cofactor bound as an internal aldimine. This structure contrasts with other eTA structures obtained at physiological pH that show products or substrates bound as PLP-external aldimines. The non-productive binding at low-pH is due to an unusual substrate serine binding orientation in which the α-amino group and carboxylate group are in the wrong positions (relative to the active site residues) as a result of protonation of the α-amino group of the serine, as well as the active site histidines, His83 and His126. Protonation of these residues prevents the characteristic nucleophilic attack of the α-amino group of substrate serine on C4′ of PLP to form the external aldimine. Our study shows that at low pH the change in charge distribution at the active site can result in substrates binding in a non-productive orientation.

Fast Atomic Charge Calculation for Implementation into a Polarizable Force Field and Application to an Ion Channel Protein

Polarization of atoms plays a substantial role in molecular interactions. Class I and II force fields mostly calculate with fixed atomic charges which can cause inadequate descriptions for highly charged molecules, for example, ion channels or metalloproteins. Changes in charge distributions can be included into molecular mechanics calculations by various methods. Here, we present a very fast computational quantum mechanical method, the Bond Polarization Theory (BPT). Atomic charges are obtained via a charge calculation method that depend on the 3D structure of the system in a similar way as atomic charges ofab initiocalculations. Different methods of population analysis and charge calculation methods and their dependence on the basis set were investigated. A refined parameterization yielded excellent correlation ofR=0.9967. The method was implemented in the force field COSMOS-NMR and applied to the histidine-tryptophan-complex of the transmembrane domain of the M2 protein channel of influenza A virus. Our calculations show that moderate changes of side chain torsion angleχ1and small variations ofχ2of Trp-41 are necessary to switch from the inactivated into the activated state; and a rough two-side jump model of His-37 is supported for proton gating in accordance with a flipping mechanism.

Heparan sulfate phage display antibodies recognise epitopes defined by a combination of sugar sequence and cation binding.

Phage display antibodies are widely used to follow heparan sulfate (HS) expression in tissues and cells. We demonstrate by ELISA, that cations alter phage display antibody binding profiles to HS and this is mediated by changes in polysaccharide conformation, demonstrated by circular dichroism spectroscopy. Native HS structures, expressed on the cell surfaces of neuroblastoma and fibroblast cells, also exhibited altered antibody binding profiles following exposure to low mM concentrations of these cations. Phage display antibodies recognise conformationally-defined HS epitopes, rather than sequence alone, as has been assumed, and resemble proteins in being sensitive to changes in both charge distribution and conformation following binding of cations to HS polysaccharides.

Gated supramolecular chemistry in hybrid mesoporous silica nanoarchitectures: controlled delivery and molecular transport in response to chemical, physical and biological stimuli.

This review presents and discusses recent advances in the emerging field of "gated nanochemistry", outlining the substantial progress made so far. The development of hybrid mesoporous silica with complex tailored pore nanoarchitectures bridges the gap between molecular materials and the requirements of nanodevices for controlled nanoscale chemistry. In the last decade, membranes, particles and thin film porous architectures have been designed, synthesized and selectively modified by molecular, polymeric, organometallic or biologically active groups. The exquisite manipulation of mesopore morphology and interconnection combined with molecular or supramolecular functionalities, and the intrinsic biological compatibility of silica have made these materials a potential platform for selective sensing and drug delivery. The wide répertoire of these hard-soft architectures permit us to envisage sophisticated intelligent nano-systems that respond to a variety of external stimuli such as pH, redox potential, molecule concentration, temperature, or light. Transduction of these stimuli into a predefined response implies exploiting spatial and physico-chemical effects such as charge distribution, steric constraints, equilibria displacements, or local changes in ionic concentration, just to name a few examples. As expected, this "positional mesochemistry" can be only attained through the concerted control of assembly, surface tailoring and, confinement conditions, thus giving birth to a new class of stimuli-responsive materials with modulable transport properties. As a guiding framework the emerging field of "gated nanochemistry" offers methodologies and tools for building up stimuli-sensitive porous architectures equipped with switchable entities whose transport properties can be triggered at will. The gated nanoscopic hybrid materials discussed here not only herald a new era in the integrative design of "smart" drug delivery systems, but also give the reader a perspective of the promising future in the development of mesoporous platforms that can control mass transport on command through the combination of flexible supramolecular routes, with implications on health, environment and energy.

Catalytic Oxidative Cyclization of 2'-Arylbenzaldehyde Oxime Ethers under Photoinduced Electron Transfer Conditions.

A series of 2'-arylbenzaldehyde oxime ethers were synthesized and shown to generate the corresponding phenanthridines upon irradiation in the presence of 9,10-dicyanoanthracene in acetonitrile. Mechanistic studies suggest that the oxidative cyclization reaction sequence is initiated by an electron transfer step followed by nucleophilic attack of the aryl ring onto the nitrogen of the oxime ether. A concave downward Hammett plot is presumably the result of a change in charge distribution in the radical cation species with strongly electron-donating substituents that yields a less electrophilic nitrogen atom and a decreased amount of cyclized product. The reaction is selective (no nitrile byproduct is formed unlike other photochemical reactions involving aldoxime ethers) as well as regiospecific when using 2'-aryl groups with meta-substituents, making this reaction a useful alternative for preparing substituted phenanthridines.

Multipole order and global/site symmetry in the hidden-order phase ofURu2Si2

On the basis of group theory and the first-principles calculations, we investigate high-rank multipole orderings in URu2Si2, which have been proposed as a genuine primary order parameter in the hidden order phase below 17.5K. We apply Shubnikov group theory to the multipole ordered states characterized by the wave vector Q = (0, 0, 1) and specify the global/site symmetry and the secondary order parameters, such as induced dipole moments and change in charge distribution. We find that such antiferroic magnetic multipole orderings have particularly advantageous to conceal the primary order parameter due to preserving high symmetry in charge distribution. Experimental observations of the inherent low-rank multipoles, which are explicitly classified in this paper, will be key pieces to understand the puzzling hidden order phase.

Rigid Medium Effects on Photophysical Properties of MLCT Excited States of Polypyridyl Os(II) Complexes in Polymerized Poly(ethylene glycol)dimethacrylate Monoliths

Higher-energy emissions from the metal-to-ligand charge-transfer (MLCT) excited states of a series of polypyridyl Os(II) complexes were observed at the fluid-to-film transition in PEG-DMA550. The higher-energy excited states, caused by a "rigid medium effect" in the film, led to enhanced emission quantum yields and longer excited-state lifetimes. Detailed analyses of spectra and excited-state dynamics by Franck-Condon emission spectral analysis and application of the energy gap law for nonradiative excited-state decay reveal that the rigid medium effect arises from the inability of part of the local medium dielectric environment to respond to the change in charge distribution in the excited state during its lifetime. Enhanced excited-state lifetimes are consistent with qualitative and quantitative predictions of the energy gap law.

Steering the excited state dynamics of a photoactive yellow protein chromophore analogue with external electric fields

The first excited state of the Photoactive Yellow Protein chromophore exhibits a strong charge transfer character and the dipole moments of the excited and ground states differ significantly. Furthermore, the excited state charge distribution changes during the isomerization of this chromophore. These observations suggest that external electric fields can be used to control photo-isomerization, providing a new concept for developing photochromic devices, such as e-paper or optical memory. To test this idea, we performed excited state dynamics simulations and static calculations of a PYP chromophore analogue (pCK−) in an external electric field. By adjusting direction and strength of the field, we were able to control both selectivity (i.e., which bond isomerizes) and efficiency (excited state lifetime) of the isomerization process. Simulations like these could potentially be useful in validating whether a given chromophore could be suitable for electrochromic applications.

The Second-Order Polarization Propagator Approximation (SOPPA) method coupled to the polarizable continuum model

We present an implementation of the Polarizable Continuum Model (PCM) in combination with the Second-Order Polarization Propagator Approximation (SOPPA) electronic structure method. In analogy with the most common way of designing ground state calculations based on a Second-Order Møller–Plesset (MP2) wave function coupled to PCM, we introduce dynamical PCM solvent effects only in the Random Phase Approximation (RPA) part of the SOPPA response equations while the static solvent contribution is kept in both the RPA terms as well as in the higher order correlation matrix components of the SOPPA response equations. By dynamic terms, we refer to contributions that describe a change in environmental polarization which, in turn, reflects a change in the core molecular charge distribution upon an electronic excitation. This new combination of methods is termed PCM–SOPPA/RPA. We apply this newly defined method to the challenging cases of solvent effects on the lowest and intense electronic transitions in o-, m- and p-nitroaniline and o-, m- and p-nitrophenol and compare the performance of PCM–SOPPA/RPA with more conventional approaches. Compared to calculations based on time-dependent density functional theory employing a range-separated exchange–correlation functional, we find the PCM–SOPPA/RPA approach to be slightly superior with respect to systematicity. On the other hand, the absolute values of the predicted excitation energies are largely underestimated. This – however – is a well-know feature of the SOPPA model itself and is not connected to its combination with the PCM.

Expression of the Orphan Cytosolic Sulfotransferase SULT1C3 in Human Intestine: Characterization of the Transcript Variant and Implications for Function

The cystolic sulfotransferse 1C3 (SULT1C3) gene was identified by computational analysis of the human genome and suggested to contain duplications of its last two exons (7a/b and 8a/b). Although the SULT1C3 isoform containing the more downstream exons 7b and 8b (SULT1C3d) has been expressed in Escherichia coli, crystallized, and characterized for activity, there is currently no evidence that SULT1C3 is expressed in any human tissue. Using reverse-transcription polymerase chain reaction, we detected SULT1C3 mRNA in the colorectal adenocarcinoma cell line (LS180), colon, and small intestine, but the amplified fragment contained the more upstream exons 7a and 8a. 3'-Rapid amplification of cDNA ends (RACE) confirmed that the SULT1C3 transcript expressed in LS180 cells contained exons 7a/8a, whereas 5'-RACE identified a noncoding exon 1. Full-length SULT1C3 transcript containing exons 7a/8a was amplified from LS180 and intestinal RNA, and in vitro transcription-translation of the cloned cDNA indicated that translation primarily began at the first of three in-frame ATG codons. Since SULT1C3 containing exons 7a/8a (SULT1C3a) would differ by 30 amino acids from SULT1C3d containing exons 7b/8b, we considered the functional implications of expressing one or the other isoform by generating structural models based on the reported crystal structure for SULT1C3d. Comparison of the structures indicated that five of the residues forming the substrate-binding pocket differed between the two isoforms, resulting in a change in both electron density and charge distribution along the inner wall of the substrate-binding pocket. These data indicate that SULT1C3 is expressed in human intestine but suggest that the expressed isoform is likely to differ functionally from the isoform that has been previously characterized.

Mass-related inversion symmetry breaking and phonon self-energy renormalization in isotopically labeled AB-stacked bilayer graphene.

A mass-related symmetry breaking in isotopically labeled bilayer graphene (2LG) was investigated during in-situ electrochemical charging of AB stacked (AB-2LG) and turbostratic (t-2LG) layers. The overlap of the two approaches, isotopic labeling and electronic doping, is powerful tool and allows to tailor, independently and distinctly, the thermal-related and transport-related phenomena in materials, since one can impose different symmetries for electrons and phonons in these systems. Variations in the system's phonon self-energy renormalizations due to the charge distribution and doping changes could be analyzed separately for each individual layer. Symmetry arguments together with first-order Raman spectra show that the single layer graphene (1LG), which is directly contacted to the electrode, has a higher concentration of charge carriers than the second graphene layer, which is not contacted by the electrode. These different charge distributions are reflected and demonstrated by different phonon self-energy renormalizations of the G modes for AB-2LG and for t-2LG.

Diffusion of ionic and non-ionic contrast agents in articular cartilage with increased cross-linking—Contribution of steric and electrostatic effects

ObjectiveTo investigate the effect of threose-induced collagen cross-linking on diffusion of ionic and non-ionic contrast agents in articular cartilage. DesignOsteochondral plugs (Ø=6mm) were prepared from bovine patellae and divided into two groups according to the contrast agent to be used in contrast enhanced computed tomography (CECT) imaging: (I) anionic ioxaglate and (II) non-ionic iodixanol. The groups I and II contained 7 and 6 sample pairs, respectively. One of the paired samples served as a reference while the other was treated with threose to induce collagen cross-linking. The equilibrium partitioning of the contrast agents was imaged after 24h of immersion. Fixed charge density (FCD), water content, contents of proteoglycans, total collagen, hydroxylysyl pyridinoline (HP), lysyl pyridinoline (LP) and pentosidine (Pent) cross-links were determined as a reference. ResultsThe equilibrium partitioning of ioxaglate (group I) was significantly (p=0.018) lower (−23.4%) in threose-treated than control samples while the equilibrium partitioning of iodixanol (group II) was unaffected by the threose-treatment. FCD in the middle and deep zones of the cartilage (p<0.05) and contents of Pent and LP (p=0.001) increased significantly due to the treatment. However, the proteoglycan concentration was not systematically altered after the treatment. Water content was significantly (−3.5%, p=0.007) lower after the treatment. ConclusionsSince non-ionic iodixanol showed no changes in partition after cross-linking, in contrast to anionic ioxaglate, we conclude that the cross-linking induced changes in charge distribution have greater effect on diffusion compared to the cross-linking induced changes in steric hindrance.

Plasma-formation dynamics in intense laser-droplet interaction.

We study the ionization dynamics in intense laser-droplet interaction using three-dimensional, relativistic particle-in-cell simulations. Of particular interest is the laser intensity and frequency regime for which initially transparent, wavelength-sized targets are not homogeneously ionized. Instead, the charge distribution changes both in space and in time on a subcycle scale. One may call this the extreme nonlinear Mie-optics regime. We find that--despite the fact that the plasma created at the droplet surface is overdense--oscillating electric fields may penetrate into the droplet under a certain angle, ionize, and propagate in the just generated plasma. This effect can be attributed to the local field enhancements at the droplet surface predicted by standard Mie theory. The penetration of the fields into the droplet leads to the formation of a highly inhomogeneous charge density distribution in the droplet interior, concentrated mostly in the polarization plane. We present a self-similar, exponential fit of the fractional ionization degree which depends only on a dimensionless combination of electric field amplitude, droplet radius, and plasma frequency with only a weak dependence on the laser frequency in the overdense regime.

Hydrogen adsorption capacity of adatoms on double carbon vacancies of graphene: A trend study from first principles

Structural stability and hydrogen adsorption capacity are two key quantities in evaluating the potential of metal-adatom decorated graphene for hydrogen storage and related devices. We have carried out extensive density functional theory calculations for the adsorption of hydrogen molecules on 12 different adatom (Ag, Au, Ca, Li, Mg, Pd, Pt, Sc, Sr, Ti, Y, and Zr) decorated graphene surfaces where the adatoms are found to be stabilized on double carbon vacancies, thus overcoming the ``clustering problem'' that occurs for adatoms on pristine graphene. Ca and Sr are predicted to bind the greatest number, namely six, of H${}_{2}$ molecules. We find an interesting correlation between the hydrogen capacity and the change of charge distribution with increasing H${}_{2}$ adsorption, where Ca, Li, Mg, Sc, Ti, Y, Sr, and Zr adatoms are partial electron donors and Ag, Au, Pd, and Pt are partial electron acceptors. The ``18-electron rule'' for predicting maximum hydrogen capacity is found not to be a reliable indicator for these systems.