Structure-based computational study of the hydrolysis of New Delhi metallo-ß-lactmase-1.

New Delhi metallo-ß-lactmase-1 (NDM-1) is an enzyme that confers antibiotic resistance to bacteria and is thus a serious threat to human health. Almost all clinically available ß-lactam antibiotics can be hydrolyzed by NDM-1. To determine the mechanism behind the wide substrate diversity and strong catalytic ability of NDM-1, we explored the molecular interactions between NDM-1 and different ß-lactam antibiotics using computational methods. Molecular dynamics simulations and binding free energy calculations were performed on enzyme-substrate (ES) complex models of NDM-1-Meropenem, NDM-1-Nitrocefin, and NDM-1-Ampicillin constructed by molecular docking. Our computational results suggest that mutant residues Ile35 and Lys216, and active site loop L1 residues 65-73 in NDM-1 play crucial roles in substrate recognition and binding. The results of our study provide new insights into the mechanism behind the enhanced substrate binding and wider substrate spectrum of NDM-1 compared with its homologous enzymes CcrA and IMP-1. These insights may be useful in the discovery and design of specific and potent inhibitors against NDM-1.

A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-ß-lactamase-1.

New Delhi metallo-ß-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known ß-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing ß-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the ß-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem ß-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.

Diverse genome structures of Salmonella paratyphi C.

BACKGROUND: Salmonella paratyphi C, like S. typhi, is adapted to humans and causes typhoid fever. Previously we reported different genome structures between two strains of S. paratyphi C, which suggests that S. paratyphi C might have a plastic genome (large DNA segments being organized in different orders or orientations on the genome). As many but not all host-adapted Salmonella pathogens have large genomic insertions as well as the supposedly resultant genomic rearrangements, bacterial genome plasticity presents an extraordinary evolutionary phenomenon. Events contributing to genomic plasticity, especially large insertions, may be associated with the formation of particular Salmonella pathogens. RESULTS: We constructed a high resolution genome map in S. paratyphi C strain RKS4594 and located four insertions totaling 176 kb (including the 90 kb SPI7) and seven deletions totaling 165 kb relative to S. typhimurium LT2. Two rearrangements were revealed, including an inversion of 1602 kb covering the ter region and the translocation of the 43 kb I-CeuI F fragment. The 23 wild type strains analyzed in this study exhibited diverse genome structures, mostly as a result of recombination between rrn genes. In at least two cases, the rearrangements involved recombination between genomic sites other than the rrn genes, possibly homologous genes in prophages. Two strains had a 20 kb deletion between rrlA and rrlB, which is a highly conservative region and no deletion has been reported in this region in any other Salmonella lineages. CONCLUSION: S. paratyphi C has diverse genome structures among different isolates, possibly as a result of large genomic insertions, e.g., SPI7. Although the Salmonella typhoid agents may not be more closely related among them than each of them to other Salmonella lineages, they may have evolved in similar ways, i.e., acquiring typhoid-associated genes followed by genome structure rearrangements. Comparison of multiple Salmonella typhoid agents at both single sequenced genome and population levels will facilitate the studies on the evolutionary process of typhoid pathogenesis, especially the identification of typhoid-associated genes.

Dissociative adsorption of carbon monoxide on Mo(110): first-principles theory.

The adsorption and dissociation of carbon monoxide on Mo (110) surface is studied with density functional theory. The results at different sites (atop, short bridge, long bridge, and hollow) are presented. The hollow site is found to be the most stable adsorption site for CO. The CO molecule is found to adsorb in end-on configurations (alpha states) at high coverage and inclined configurations (beta states) at low coverage. The dissociation activation energy from beta states is found to be approximately 1 eV lower than from alpha state. The adsorption of dissociation products, C and O, on Mo(110) has also been studied. The most stable adsorption site for C and O is long bridge and hollow site, respectively. The adsorption of C and O at low coverage is, in general, stronger than at high coverage, which is partly responsible for the high reactivity of CO dissociation at low coverage, since the binding energy of CO is not very sensitive to the coverage.

Predicting facile epoxidation of the diamond (100) surface by dioxiranes and subsequent ring-opening reactions with nucleophiles.

By means of density functional theory coupled with effective cluster models, we have theoretically predicted the viability of epoxidation of the diamond (100) surface by organic dioxiranes. In addition, subsequent ring-opening reactions of the as-formed epoxide surface species with some nucleophiles, including water, ammonia, and alcohol, have also been explored. The facile epoxidation of diamond (100) by dioxiranes presents a new alternative for oxidation of the diamond (100) surface. More importantly, the as-formed epoxide-like surface species would be a useful springboard for further functionalizations of the diamond surface given the well-known abundant chemistry of organic epoxides. Therefore, this approach provides another new route to chemical functionalization of the diamond surface, which is potentially useful for leading to the improvement of diamond behavior and constructing new hybrid diamond-based materials for wide potential applications in many fields. In perspective, implications for other theoretical work are also discussed.

Organic functionalization of the Si (100) and Ge (100) surfaces by cycloadditions of carbenes and nitrenes: a theoretical prediction.

By means of density functional theory (B3LYP/6-31G*) coupled with effective cluster models, we predict that the well-known cycloaddition reactions of carbenes and nitrenes to alkenes in organic chemistry can be employed as a new type of surface reaction to organically functionalize the Si (100) and Ge (100) surfaces at low temperature. The well-established abundance of carbenes and nitrenes addition chemistry in organic chemistry provides versatile flexibility of functionalizing the surfaces of Si (100) and Ge (100), which can potentially impart new organic functionalities to the semiconductors surface for novel applications in a diversity of fields. Our predictions strongly advance the concept of using organic reactions to modify the solid surface in a controlled manner and quite intriguing chemistry can lie in the material featuring the analogous bonding motif. In further perspective, implications for other theoretical work, regarding disilenes, digermenes, silenes, and germenes that all feature the bonding motif similar to alkenes, are also discussed.

The cycloadditions of various substituted carbenes, silylenes, and germylenes onto the diamond (100) surface: a theoretical exploration.

The cycloadditions of 21 singlet substituted carbenes, silylenes, and germylenes onto the diamond (100) surface have been theoretically studied by means of density functional theory coupled with effective cluster models. The calculated reaction energies and reaction pathways have disclosed that the substituents play an important effect on the reaction profiles for the additions of carbenes, silylenes, and germylenes onto the diamond (100) surface. Our theoretical investigations illustrate that, irrespective of carbenes, silylenes, and germylenes, the cycloadditions of those with electropositive substituents (such as H and CH(3)) onto diamond (100) are much more favorable than those with electronegative and pi-donating substituents (such as F and NH(2)) both thermodynamically and kinetically. In broad perspective, we believe that a similar reactivity trend can also be extended to that of Si (100), Ge (100), fullerene, single-walled carbon nanotube, disilenes, digermenes, silenes, and germenes because all of these materials feature an analogous bonding motif.

A theoretical study on the electronic structures of TiO2: Effect of Hartree-Fock exchange.

The effects of the Fock exchange on the geometries and electronic structures of TiO2 have been investigated by introducing a portion of Hartree-Fock (HF) exchange into the traditional density functional. Our results indicate that the functional with 13% HF exchange can correctly predict the band gap and the electronic structures of rutile TiO2, and such an approach is also suitable to describe the structural and electronic properties of anatase and brookite phases. For the TiO2 (110) surfaces, although the surface relaxations are insensitive to the variation of HF exchange, there are larger effects on the positions of the occupied surface-induced states. When 13% HF exchange is employed, the predicted band gap of the perfect surface and position of defect state of the reduced surface are consistent with the experimental values. Moreover, the electronic structures of TiO2 (110) surface are carefully reexamined by using this hybrid density functional method.

[Hepatitis B virus genotypes and alanine aminotransferase levels in HBeAg negative patients with chronic hepatitis B and liver cirrhosis].

OBJECTIVE: To investigate genotypes of the hepatitis B virus (HBV) and alanine aminotransferase (ALT) levels of HBeAg negative patients with chronic hepatitis B and liver cirrhosis. METHODS: HBV serological markers and ALT levels were detected in 62 patients with chronic hepatitis B and 41 cases with liver cirrhosis, using enzyme linked absorbent immunoassays and an enzyme method, respectively. A polymerase chain reaction of S region was used for HBV genotyping. RESULTS: Of the 62 patients with chronic hepatitis B, 21 (33.9%) were HBeAg negative, and 41 (66.1%) HBeAg positive. Among 41 cases with liver cirrhosis, 28 (68.3%) were HBeAg negative, and 13 (31.7%) HBeAg positive. Of these 62 patients with chronic hepatitis B, 53 (85.5%) were infected with HBV genotype C, and 9 (14.5%) with genotype B. Thirty-nine (95.1%) of the 41 patients with liver cirrhosis were infected with genotype C, and 2 (4.9%) with genotype B. The proportion of HBeAg negative chronic hepatitis B patients with ALT level > 40 U/L was lower than that of the HBeAg positive group (47.6% and 85.4%, respectively) (P < 0.01). The percentage of ALT levels > 40 U/L of the negative patients with liver cirrhosis was also lower as compared to that of the HBeAg positive patients, but there was no statistical difference between the two groups, because of the small sample size (P > 0.05). CONCLUSION: The proportion of HBeAg negative patients is high in the group of chronic hepatitis B and liver cirrhosis. These patients have relatively low ALT levels, and mainly have HBV genotype C infection.

Three silver iodides with zero and one-dimensional hybrid structures directed by conjugated organic templates: synthesis and theoretical study.

Under the direction of large conjugated organic cationic SDAs (structure-directing agents), three silver(I) iodides, (ipq)4(Ag2I6 x 2I2) (1), {[pql][Ag2I3]}n (2), [(npql)2(Ag4I6)]n (3) (ipq+ = N-(isopentyl)-quinolinium, pql+ = N-propyl-quinolinium, npql+ = N-(n-pentyl)-quinolinium) have been synthesized. 1 presents a zero-dimensional structure constituting of ipq+ cations, [Ag2I6]4- anions and molecular iodine. But 2 and 3 consist of one-dimensional coordination polymers that could be described as edge-sharing AgI4 tetrahedra. Electrostatic interactions between organic counter cations and inorganic moieties are present and contribute to the crystal packing. The structural differences between 1, 2 and 3 illustrate the influences of substituents of SDAs on the linkage modes of AgI4 tetrahedra. DFT calculations were carried out to reveal their electronic structures.

A series of new copper iodobismuthates: structural relationships, optical band gaps affected by dimensionality, and distinct thermal stabilities.

Three new copper iodobismuthates, red tetranuclear [n-Bu(4)N][Cu(2)(CH(3)CN)(2)Bi(2)I(10)] (1), dark-red infinite linear [Et(4)N](2n)[Cu(2)Bi(2)I(10)](n) (2), and black polymeric ladderlike [Cu(CH(3)CN)(4)](2n)[Cu(2)Bi(2)I(10)](n) (3), crystallize from solutions of BiI3 and CuI in the presence of different cations. A regular structural relationship from 0-D (1) to 1-D linear anion chains (2) to 1-D ladderlike anion chains (3) is observed. The self-assembly of the basic building unit Cu(2)Bi(2)I(10) as altered by different cations is proposed to be the driving force for their formation. The optical band gaps exhibit a structure-related decrease from 1 to 2/3, in agreement with their color changes and the density functional theory (DFT) calculation results. The electronic structures and the relationship with corresponding monobismuth analogues and the Ag-Bi isotypes are discussed on the basis of DFT calculations. In spite of their structural similarities, the compounds are distinctive thermally: 2 is stable to 230 degrees C, 1 undergoes a solvent loss at 85 degrees C to form a new phase that is thermally stable to 230 degrees C, and 3 releases a solvent molecule and decomposes at 80 degrees C into BiI(3) and CuI. The essential reasons for these differences are discussed.

Silver iodobismuthates: syntheses, structures, properties, and theoretical studies of [Bi2Ag2I10 2-]n and [Bi4Ag2I16 2-]n.

Two novel silver iodobismuthates have been obtained: (Et4N)2n-[Bi2Ag2I10]n (1) with one-dimensional infinite chains built from bimetallic tetranuclear units and (Et4N)2n[Bi4Ag2I16]n (2) with a two-dimensional 44 grid assembly of the tetranuclear Bi4I16 subunits as nodes and Ag atoms as linkages. Their optical band gaps, 2.05 and 1.93 eV, fit nicely in a size correlation of the Bi/I subunit, which is further supported by the density functional theory studies.

Spontaneous conversion between mutL and 6 bpDeltamutL in Salmonella typhimurium LT7: association with genome diversification and possible roles in bacterial adaptation.

Previously, we reported the phenomenon of genome diversification in Salmonella typhimurium LT7, i.e., individual strains derived from LT7 kept changing the genome structure by inversions, translocations, duplications, and mutations. To elucidate the genetic basis, we sequenced selected genes of the mismatch repair (MMR) system for correlations between MMR defects and genome diversification. We chose S. typhimurium LT7 mutants 8111F2 and 9052D1 for mut gene sequence analyses and found that both mutants had a deletion of one of three tandem 6-bp repeats, GCTGGC GCTGGC GCTGGC, within mutL, which was designated 6 bpDeltamutL. mutS and mutH genes were unchanged in the mutants analyzed. Some sublines of 8111F2 and 9052D1 spontaneously stopped the genome diversification process at certain stages during single-colony restreaking passages, and in these strains the 6 bpDeltamutL genotype also became wild-type mutL. We conclude that conversion between mutL and 6 bpDeltamutL occurs spontaneously and that transient defects of mutL facilitate genome diversification without leading to the accumulation of multiple detrimental genetic changes. Spontaneous conversion between mutL and 6 bpDeltamutL may be an important mechanism used by bacteria to regulate genetic stability in adaptation to changing environments.

Structural characterizations and electronic properties of Ti-doped SnO2(110) surface: a first-principles study.

The Ti-doped SnO2(110) surface has been investigated by using first-principles method with a slab model. The geometrical optimizations and band-structure calculations have been performed for four possible doping models. Our results indicate that the substitution of Ti for sixfold-coordinated Sn atom at the top layer is most energetically favorable. Compared to the undoped surface, those Sn and O atoms located above Ti atom tend to move toward the bulk side. Besides the surface relaxations, the doping of Ti has significant influences on the electronic structures of SnO2(110) surface, including the value and position of minimum band gap, the components of valence and conduction bands, the distributions of the charge densities, and the work function of the surface. Furthermore, the effects introduced by the substitution of Ti atom observed in the experiments can be well explained when the sixfold-coordinated Sn atom at the first layer is replaced by Ti atom.

Functionalization of diamond (100) by organic cycloaddition reactions of nitrenes: a theoretical prediction.

[structure: see text] We predict the viability of organic cycloadditions of nitrenes onto the diamond (100) surface. This new type of surface reaction can be employed to functionalize diamond surface at low temperature, which might introduce new functionalities to the diamond surface for novel applications in a diversity of fields.

Organic functionalization of diamond (100) by addition reactions of carbene, silylene, and germylene: a theoretical prediction.

We present a theoretical prediction of the facile cycloadditions of carbene, silylene, and germylene onto the diamond (100) surface, a new type of surface reaction that can be employed to functionalize diamond surface at low temperature. This finding renders the plausibility that the diamond surface can be chemically modified by the well-known carbene addition chemistry, which might introduce new functionalities to the diamond surface for novel applications in a diversity of fields.

The adsorption and dissociation of Cl2 on the MgO (001) surface with vacancies: embedded cluster model study.

The adsorption of Cl(2) at a low-coordinated oxygen site (edge or corner site) and vacancy site (terrace, edge, corner F, F(+), or F(2+) center) has been studied by the density functional method, in conjunction with the embedded cluster models. First, we have studied the adsorption of Cl(2) at the edge and corner oxygen sites and the results show that Cl(2), energetically, is inclined to adsorb at the corner oxygen site. Moreover, similar to the most advantageous adsorption mode for Cl(2) on the MgO (001) perfect surface, the most favorable adsorption occurs when Cl(2) approaches the corner oxygen site along the normal direction. A small amount of electrons are transferred from the substrate to the antibonding orbital of the adsorbate, leading to the Cl-Cl bond strength weakened a little. Regarding Cl(2) adsorption at the oxygen vacancy site (F, F(+), or F(2+) center), both large adsorption energies and rather much elongation of the Cl-Cl bond length have been obtained, in particular at the corner oxygen vacancy site, with concurrently large amounts of electrons transferred from the substrate to the antibonding orbital of Cl(2). It suggests, at the oxygen vacancy site, that Cl(2) prefers to dissociate into Cl subspecies. And the potential energy surface indicates that the dissociation process of molecular Cl(2) to atomic Cl is virtually barrierless.