Toward the Next Generation of Density Functionals: Escaping the Zero-Sum Game by Using the Exact-Exchange Energy Density.

ConspectusKohn-Sham density functional theory (KS DFT) is arguably the most widely applied electronic-structure method with tens of thousands of publications each year in a wide variety of fields. Its importance and usefulness can thus hardly be overstated. The central quantity that determines the accuracy of KS DFT calculations is the exchange-correlation functional. Its exact form is unknown, or better "unknowable", and therefore the derivation of ever more accurate yet efficiently applicable approximate functionals is the "holy grail" in the field. In this context, the simultaneous minimization of so-called delocalization errors and static correlation errors is the greatest challenge that needs to be overcome as we move toward more accurate yet computationally efficient methods. In many cases, an improvement on one of these two aspects (also often termed fractional-charge and fractional-spin errors, respectively) generates a deterioration in the other one. Here we report on recent notable progress in escaping this so-called "zero-sum-game" by constructing new functionals based on the exact-exchange energy density. In particular, local hybrid and range-separated local hybrid functionals are discussed that incorporate additional terms that deal with static correlation as well as with delocalization errors. Taking hints from other coordinate-space models of nondynamical and strong electron correlations (the B13 and KP16/B13 models), position-dependent functions that cover these aspects in real space have been devised and incorporated into the local-mixing functions determining the position-dependence of exact-exchange admixture of local hybrids as well as into the treatment of range separation in range-separated local hybrids. While initial functionals followed closely the B13 and KP16/B13 frameworks, meanwhile simpler real-space functions based on ratios of semilocal and exact-exchange energy densities have been found, providing a basis for relatively simple and numerically convenient functionals. Notably, the correction terms can either increase or decrease exact-exchange admixture locally in real space (and in interelectronic-distance space), leading even to regions with negative admixture in cases of particularly strong static correlations. Efficient implementations into a fast computer code (Turbomole) using seminumerical integration techniques make such local hybrid and range-separated local hybrid functionals promising new tools for complicated composite systems in many research areas, where simultaneously small delocalization errors and static correlation errors are crucial. First real-world application examples of the new functionals are provided, including stretched bonds, symmetry-breaking and hyperfine coupling in open-shell transition-metal complexes, as well as a reduction of static correlation errors in the computation of nuclear shieldings and magnetizabilities. The newest versions of range-separated local hybrids (e.g., ωLH23tdE) retain the excellent frontier-orbital energies and correct asymptotic exchange-correlation potential of the underlying ωLH22t functional while improving substantially on strong-correlation cases. The form of these functionals can be further linked to the performance of the recent impactful deep-neural-network "black-box" functional DM21, which itself may be viewed as a range-separated local hybrid.

Life Sciences in the Ticino: Two Scientists - Two Stories.

Luca Varani, PhD, a group leader in Structural Biology at the Institute for Research in Biomedicine, Bellinzona, and Marco Brini, founder and CEO of EnvEve SA, in the Tecnopolo in Manno, describe their life sciences background, their careers and why they percieve their ideal situation being a basic scientist who wants to remain in science, or being an entrepreneur respectively.

Innovate with the CTI National Thematic Networks.

Winning in the global market place with brilliant innovations is the recipe for success for the Swiss economy. Indeed, Switzerland always stands out in the global rankings when it comes to innovation. Yet there is nothing as dangerous as to rest on one's laurels, and this is particularly true for R&D-based businesses. For this reason CTI, the Commission for Technology and Innovation, offers Swiss companies quick and effective access to knowledge available at Swiss public research institutions, and to international R&D programs promoting application-oriented research. Knowledge and technology transfer are promoted - via its KTT support - through National Thematic Networks (NTNs), Innovation Mentors and information platforms. The following article highlights the activities of the National Thematic Networks and invites Swiss companies and research institutes to benefit from the multiple offers and services available.

Accurate Ionization Potentials, Electron Affinities, and Band Gaps from the ωLH22t Range-Separated Local Hybrid Functional: No Tuning Required.

The optimal tuning (OT) of range-separated hybrid (RSH) functionals has been proposed as the currently most accurate DFT-based way to compute the relevant quantities required for charge-transfer processes in organic chromophores used in organic photovoltaics and related fields. The main drawback of OT-RSHs is that the system-specific tuning of the range-separation parameter is not size-consistent. It therefore also lacks transferability, e.g., when considering processes involving orbitals not involved in the tuning or for reactions between different chromophores. Here we show that the recently reported ωLH22t range-separated local hybrid functional provides ionization energies, electron affinities, and fundamental gaps on par with OT-RSH treatments, approaching the quality of GW results, without any need for system-specific tuning. This holds from relevant organic chromophores of varying sizes all the way to atomic electron affinities. ωLH22t also gives excellent outer-valence quasiparticle spectra and is a generally accurate functional for both main-group and transition-metal energetics, as well as for a variety of excitation types. Range-separated local hybrid functionals are suggested as promising new quantum-chemical tools in molecular electronics.

Range-Separated Local Hybrid Functionals with Small Fractional-Charge and Fractional-Spin Errors: Escaping the Zero-Sum Game of DFT Functionals.

Extending recent developments on strong-correlation (sc) corrections to local hybrid functionals to the recent accurate ωLH22t range-separated local hybrid, a series of highly flexible strong-correlation-corrected range-separated local hybrids (scRSLHs) has been constructed and evaluated. This has required the position-dependent reduction of both short- and long-range exact-exchange admixtures in regions of space characterized by strong static correlations. Using damping procedures provides scRSLHs that retain largely the excellent performance of ωLH22t for weakly correlated situations and, in particular, for accurate quasiparticle energies of a wide variety of systems while reducing dramatically static-correlation errors, e.g., in stretched-bond situations. An additional correction to the local mixing function to reduce delocalization errors in abnormal open-shell situations provides further improvements in thermochemical and kinetic parameters, making scRSLH functionals such as ωLH23tdE or ωLH23tdP promising tools for complex molecular or condensed-phase systems, where low fractional-charge and fractional-spin errors are simultaneously important. The proposed rung 4 functionals thereby largely escape the usual zero-sum game between these two quantities and are expected to open new areas of accurate computations by Kohn-Sham DFT. At the same time, they require essentially no extra computational effort over the underlying ωLH22t functional, which means that their use is only moderately more demanding than that of global, local, or range-separated hybrid functionals.

Full Implementation, Optimization, and Evaluation of a Range-Separated Local Hybrid Functional with Wide Accuracy for Ground and Excited States.

We report the first full and efficient implementation of range-separated local hybrid functionals (RSLHs) into the TURBOMOLE program package. This enables the computation of ground-state energies and nuclear gradients as well as excitation energies. Regarding the computational effort, RSLHs scale like regular local hybrid functionals (LHs) with system or basis set size and increase timings by a factor of 2-3 in total. An advanced RSLH, ωLH22t, has been optimized for atomization energies and reaction barriers. It is an extension of the recent LH20t local hybrid and is based on short-range PBE and long-range HF exchange-energy densities, a pig2 calibration function to deal with the gauge ambiguity of exchange-energy densities, and reoptimized B95c correlation. ωLH22t has been evaluated for a wide range of ground-state and excited-state quantities. It further improves upon the already successful LH20t functional for the GMTKN55 main-group energetics test suite, and it outperforms any global hybrid while performing close to the top rung-4 functional, ωB97M-V, for these evaluations when augmented by D4 dispersion corrections. ωLH22t performs excellently for transition-metal reactivity and provides good balance between delocalization errors and left-right correlation for mixed-valence systems, with a somewhat larger bias toward localized states compared to LH20t. It approaches the accuracy of the best local hybrids to date for core, valence singlet and triplet, and Rydberg excitation energies while improving strikingly on intra- and intermolecular charge-transfer excitations, comparable to the most successful range-separated hybrids available.

TURBOMOLE: Today and Tomorrow.

TURBOMOLE is a highly optimized software suite for large-scale quantum-chemical and materials science simulations of molecules, clusters, extended systems, and periodic solids. TURBOMOLE uses Gaussian basis sets and has been designed with robust and fast quantum-chemical applications in mind, ranging from homogeneous and heterogeneous catalysis to inorganic and organic chemistry and various types of spectroscopy, light-matter interactions, and biochemistry. This Perspective briefly surveys TURBOMOLE's functionality and highlights recent developments that have taken place between 2020 and 2023, comprising new electronic structure methods for molecules and solids, previously unavailable molecular properties, embedding, and molecular dynamics approaches. Select features under development are reviewed to illustrate the continuous growth of the program suite, including nuclear electronic orbital methods, Hartree-Fock-based adiabatic connection models, simplified time-dependent density functional theory, relativistic effects and magnetic properties, and multiscale modeling of optical properties.

Investigating the role of GLUL as a survival factor in cellular adaptation to glutamine depletion via targeted stable isotope resolved metabolomics.

Cellular glutamine synthesis is thought to be an important resistance factor in protecting cells from nutrient deprivation and may also contribute to drug resistance. The application of ?targeted stable isotope resolved metabolomics" allowed to directly measure the activity of glutamine synthetase in the cell. With the help of this method, the fate of glutamine derived nitrogen within the biochemical network of the cells was traced. The application of stable isotope labelled substrates and analyses of isotope enrichment in metabolic intermediates allows the determination of metabolic activity and flux in biological systems. In our study we used stable isotope labelled substrates of glutamine synthetase to demonstrate its role in the starvation response of cancer cells. We applied 13C labelled glutamate and 15N labelled ammonium and determined the enrichment of both isotopes in glutamine and nucleotide species. Our results show that the metabolic compensatory pathways to overcome glutamine depletion depend on the ability to synthesise glutamine via glutamine synthetase. We demonstrate that the application of dual-isotope tracing can be used to address specific reactions within the biochemical network directly. Our study highlights the potential of concurrent isotope tracing methods in medical research.

Analysing central metabolism in ultra-high resolution: At the crossroads of carbon and nitrogen.

BACKGROUND: Cancer cell metabolism can be characterised by adaptive metabolic alterations, which support abnormal proliferative cell growth with high energetic demand. De novo nucleotide biosynthesis is essential for providing nucleotides for RNA and DNA synthesis, and drugs targeting this biosynthetic pathway have proven to be effective anticancer therapeutics. Nevertheless, cancers are often able to circumvent chemotherapeutic interventions and become therapy resistant. Our understanding of the changing metabolic profile of the cancer cell and the mode of action of therapeutics is dependent on technological advances in biochemical analysis. SCOPE OF REVIEW: This review begins with information about carbon- and nitrogen-donating pathways to build purine and pyrimidine moieties in the course of nucleotide biosynthesis. We discuss the application of stable isotope resolved metabolomics to investigate the dynamics of cancer cell metabolism and outline the benefits of high-resolution accurate mass spectrometry, which enables multiple tracer studies. CONCLUSION: With the technological advances in mass spectrometry that allow for the analysis of the metabolome in high resolution, the application of stable isotope resolved metabolomics has become an important technique in the investigation of biological processes. The literature in the area of isotope labelling is dominated by 13C tracer studies. Metabolic pathways have to be considered as complex interconnected networks and should be investigated as such. Moving forward to simultaneous tracing of different stable isotopes will help elucidate the interplay between carbon and nitrogen flow and the dynamics of de novo nucleotide biosynthesis within the cell.