Assessment of time-dependent density functional theory with the restricted excitation space approximation for excited state calculations of large systems

The restricted excitation subspace approximation is explored as a basis to reduce the memory storage required in linear response time-dependent density functional theory (TDDFT) calculations within the Tamm-Dancoff approximation. It is shown that excluding the core orbitals and up to 70% of the virtual orbitals in the construction of the excitation subspace does not result in significant changes in computed UV/vis spectra for large molecules. The reduced size of the excitation subspace greatly reduces the size of the subspace vectors that need to be stored when using the Davidson procedure to determine the eigenvalues of the TDDFT equations. Furthermore, additional screening of the two-electron integrals in combination with a reduction in the size of the numerical integration grid used in the TDDFT calculation leads to significant computational savings. The use of these approximations represents a simple approach to extend TDDFT to the study of large systems and make the calculations increasingly tractable using modest computing resources

Kohn-Sham density functional theory calculations of non-resonant and resonant X-ray emission spectroscopy

The accuracy of non-resonant and resonant (resonant inelastic X-ray scattering) X-ray emission spectra simulated based upon Kohn-Sham density functional theory is assessed. Accurate non-resonant X-ray emission spectra with the correct energy scale are obtained when short-range corrected exchange-correlation functionals designed for the calculation of X-ray absorption spectroscopy are used. It is shown that this approach can be extended to simulate resonant inelastic X-ray scattering by using a reference determinant that describes a core-excited state. For this spectroscopy, it is found that a standard hybrid functional, B3LYP, gives accurate spectra that reproduce the features observed in experiment. However, the ability to correctly describe subtle changes in the spectra arising from different intermediate states is more challenging and requires averaging over conformations from a molecular dynamics simulation. Overall, it is demonstrated that accurate non-resonant and resonant X ray emission spectra can be simulated directly from Kohn-Sham density functional theory

Calculating excited state properties using Kohn-Sham density functional theory

The accuracy of excited states calculated with Kohn-Sham density functional theory using the maximum overlap method has been assessed for the calculation of adiabatic excitation energies, excited state structures, and excited state harmonic and anharmonic vibrational frequencies for open-shell singlet excited states. The computed Kohn-Sham adiabatic excitation energies are improved significantly by post self-consistent-field spin-purification, but remain too low compared with experiment with a larger error than time-dependent density functional theory. Excited state structures and vibrational frequencies are also improved by spin-purification. The structures show a comparable accuracy to time-dependent density functional theory, while the harmonic vibrational frequencies are found to be more accurate for the majority of vibrational modes. The computed harmonic vibrational frequencies are also further improved by perturbative anharmonic corrections, suggesting a good description of the potential energy surface. Overall, excited state Kohn-Sham density functional theory is shown to provide an efficient method for the calculation of excited state structures and vibrational frequencies in open-shell singlet systems, and provides a promising technique that can be applied to study large systems

Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea

The new superbug Neisseria gonorrhoeae has retained resistance to antimicrobials previously recommended for first-line treatment and has now demonstrated its capacity to develop resistance to the extended-spectrum cephalosporin, ceftriaxone, the last remaining option for first-line empiric treatment of gonorrhea. An era of untreatable gonorrhea may be approaching, which represents an exceedingly serious public health problem. Herein, we review the evolution, origin and spread of antimicrobial resistance and resistance determinants (with a focus on extended-spectrum cephalosporins) in N. gonorrhoeae, detail the current situation regarding verified treatment failures with extended-spectrum cephalosporins and future treatment options, and highlight essential actions to meet the large public health challenge that arises with the possible emergence of untreatable gonorrhea. Essential actions include: implementing action/response plans globally and nationally; enhancing surveillance of gonococcal antimicrobial resistance, treatment failures and antimicrobial use/misuse; and improving prevention, early diagnosis and treatment of gonorrhea. Novel treatment strategies, antimicrobials (or other compounds) and, ideally, a vaccine must be developed

The impact of sulfur functionalisation on nitrogen-based ionic liquid cations

It has been demonstrated that bonding and interactions within ionic liquids (ILs) can be elegantly tuned by manipulation of structure and the the introduction of functional groups. Here we use XPS to investigate the impact of sulfur containing substituents on the electronic structure of a series N-based cations, all with a common anion, [NTf2]-. The experiments reveal complexity and perturbation of delocalised systems which cannot be easily interpretated by NMR and XPS alone, DFT provides critical insight into bonding and underpins the assignment of spectra and development of deconstruction models for each system studied

Alanine 501 Mutations in Penicillin-Binding Protein 2 from Neisseria gonorrhoeae : Structure, Mechanism, and Effects on Cephalosporin Resistance and Biological Fitness

Resistance of Neisseria gonorrhoeae to expanded-spectrum cephalosporins such as ceftriaxone and cefixime has increased markedly in the past decade. The primary cephalosporin resistance determinant is a mutated penA gene, which encodes the essential peptidoglycan transpeptidase, penicillin-binding protein 2 (PBP2). Decreased susceptibility and resistance can be conferred by mosaic penA alleles containing upward of 60 amino acid changes relative to wild-type PBP2, or by nonmosaic alleles with relatively few mutations, the most important of which occurs at Ala501 located near the active site of PBP2. Recently, fully cefixime- and ceftriaxone-resistant clinical isolates that harbored a mosaic penA allele with an A501P mutation were identified. To examine the potential of mutations at Ala501 to increase resistance to expanded-spectrum cephalosporins, we randomized codon 501 in a mosaic penA allele and transformed N. gonorrhoeae to increased cefixime resistance. Interestingly, only five substitutions of Ala501 (A501V, A501T, A501P, A501R, and A501S) that increased resistance and preserved essential transpeptidase function were isolated. To understand their structural implications, these mutations were introduced into the nonmosaic PBP2-6140CT, which contains four C-terminal mutations present in PBP2 from the penicillin-resistant strain FA6140. The crystal structure of PBP2-6140CT-A501T was determined and revealed ordering of a loop near the active site and a new hydrogen bond involving Thr501 that connects the loop and the SxxK conserved active site motif. The structure suggests that increased rigidity in the active site region is a mechanism for cephalosporin resistance mediated by Ala501 mutations in PBP2

Molecular and Structural Analysis of Mosaic Variants of Penicillin-Binding Protein 2 Conferring Decreased Susceptibility to Expanded-Spectrum Cephalosporins in Neisseria gonorrhoeae : Role of Epistatic Mutations

Mutations in penicillin-binding protein 2 (PBP 2) encoded by mosaic penA alleles are critical for intermediate resistance to the expanded-spectrum cephalosporins ceftriaxone and cefixime in Neisseria gonorrhoeae. Three of the ~60 mutations present in mosaic alleles of penA, G545S, I312M, and V316T, have been reported to be responsible for increased resistance, especially to cefixime (Takahata et al. 2006. Antimicrob Agents Chemother 50:3638-45). However, we observed that the minimum inhibitory concentrations (MICs) of penicillin, ceftriaxone, and cefixime for a wild type strain (FA19) containing a penA gene with these three mutations increased only 1.5-, 1.5-, and 3.5-fold, respectively. In contrast, when these three mutations in a mosaic penA allele (penA35) were reverted back to wild type and the gene transformed into FA19, the MICs of the three antibiotics were reduced to near wild type levels. Thus, these three mutations display epistasis, in that their capacity to increase resistance to β-lactam antibiotics is dependent on the presence of other mutations in the mosaic alleles. We also identified an additional mutation, N512Y, that contributes to decreased susceptibility to expanded-spectrum cephalosporins. Finally, we investigated the effects of a mutation (A501V) currently found only in non-mosaic penA alleles on decreased susceptibility to ceftriaxone and cefixime, under the expectation that this mutation may arise in mosaic alleles. Transfer of the mosaic penA35 allele containing an A501V mutation into FA6140, a chromosomally mediated penicillin-resistant isolate, increased the MICs of ceftriaxone (0.4 μg/ml) and cefixime (1.2μg/ml) to levels above their respective breakpoints. The proposed structural mechanisms of these mutations are discussed in light of the recently published structure of PBP 2

Density functional theory calculations of the non-resonant and resonant X-ray emission spectroscopy of carbon fullerenes and nanotubes

The non-resonant X-ray emission spectroscopy of fullerenes and carbon nanotubes is studied with density functional theory in conjunction with short-range corrected functionals. For C60 and C70 the X-ray emission spectra are insensitive to modest structural changes, and absorption onto the fullerene cage has the greatest effect with a broader less structured band observed with the high energy ⇡ band reduced in intensity. For carbon nanotubes the X-ray emission spectra are shown to be weakly dependent on the length and chirality of the nanotube. However, some variation with the diameter of the tube is observed in both resonant and non-resonant spectra

Identification of Amino Acids Conferring High-Level Resistance to Expanded-Spectrum Cephalosporins in the penA Gene from Neisseria gonorrhoeae Strain H041

ABSTRACT The recent identification of a high-level-ceftriaxone-resistant (MIC = 2 to 4 μg/ml) isolate of Neisseria gonorrhoeae from Japan (H041) portends the loss of ceftriaxone as an effective treatment for gonococcal infections. This is of grave concern because ceftriaxone is the last remaining option for first-line empirical antimicrobial monotherapy. The penA gene from H041 ( penA41 ) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance (Ceph i ) worldwide but has 13 additional mutations compared to the mosaic penA gene from the previously studied Ceph i strain 35/02 ( penA35 ). When transformed into the wild-type strain FA19, the penA41 allele confers 300- and 570-fold increases in the MICs for ceftriaxone and cefixime, respectively. In order to understand the mechanisms involved in high-level ceftriaxone resistance and to improve surveillance and epidemiology during the potential emergence of ceftriaxone resistance, we sought to identify the minimum number of amino acid alterations above those in penA35 that confer high-level resistance to ceftriaxone. Using restriction fragment exchange and site-directed mutagenesis, we identified three mutations, A311V, T316P, and T483S, that, when incorporated into the mosaic penA35 allele, confer essentially all of the increased resistance of penA41 . A311V and T316P are close to the active-site nucleophile Ser310 that forms the acyl-enzyme complex, while Thr483 is predicted to interact with the carboxylate of the β-lactam antibiotic. These three mutations have thus far been described only for penA41 , but dissemination of these mutations in other mosaic alleles would spell the end of ceftriaxone as an effective treatment for gonococcal infections

Infrared spectroscopy of NaCl(CH3OH)n complexes in helium nanodroplets

Infrared (IR) spectra of complexes between NaCl and methanol have been recorded for the first time. These complexes were formed in liquid helium nanodroplets by consecutive pick-up of NaCl and CH3OH molecules. For the smallest NaCl(CH3OH)n complexes where n = 1-3, the IR data suggest that the lowest energy isomer is the primary product in each case. The predominant contribution to the binding comes from ionic hydrogen bonds between the OH in each methanol molecule and the chloride ion in the NaCl, as established by the large red-shift of the OH stretching bands compared with the isolated CH3OH molecule. For n ≥ 4 there is a dramatic shift from discrete vibrational bands to very broad absorption envelopes, suggesting a profound change in the structural landscape and, in particular, access to multiple low-energy isomers