T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery.

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER's potency and versatility.

CO2 on Graphene: Benchmarking Computational Approaches to Noncovalent Interactions.

Designing and optimizing graphene-based gas sensors in silico entail constructing appropriate atomistic representations for the physisorption complex of an analyte on an infinite graphene sheet, then selecting accurate yet affordable methods for geometry optimizations and energy computations. In this work, diverse density functionals (DFs), coupled cluster theory, and symmetry-adapted perturbation theory (SAPT) in conjunction with a range of finite and periodic surface models of bare and supported graphene were tested for their ability to reproduce the experimental adsorption energies of CO2 on graphene in a low-coverage regime. Periodic results are accurately reproduced by the interaction energies extrapolated from finite clusters to infinity. This simple yet powerful scheme effectively removes size dependence from the data obtained using finite models, and the latter can be treated at more sophisticated levels of theory relative to periodic systems. While for small models inexpensive DFs such as PBE-D3 afford surprisingly good agreement with the gold standard of quantum chemistry, CCSD(T), interaction energies closest to experiment are obtained by extrapolating the SAPT results and with nonlocal van der Waals functionals in the periodic setting. Finally, none of the methods and models reproduce the experimentally observed CO2 tilted adsorption geometry on the Pt(111) support, calling for either even more elaborate theoretical approaches or a revision of the experiment.

Metal-Free Molecular Catalysts for the Oxygen Reduction Reaction: Electron Affinity as an Activity Descriptor.

Heteroatom-doped polyaromatic hydrocarbons (or nanographenes) are promising molecular electrocatalysts for the oxygen reduction reaction (ORR). Here, we use density functional theory to investigate the first step of the ORR pathway (chemisorption) for a set of molecules with experimentally determined catalytic activities. Weak chemisorption is found for only negatively charged catalysts, and a strong correlation is observed between the computed electron affinities and experimental catalytic activities for a range of B- and B,N-doped polyaromatic hydrocarbons. The electron affinity is put forward as a simple activity descriptor of charged (activated) catalysts on an electrode.

Why Ultrafast Photoinduced CO Desorption Dominates over Oxidation on Ru(0001).

CO oxidation on Ru(0001) is a long-standing example of a reaction that, being thermally forbidden in ultrahigh vacuum, can be activated by femtosecond laser pulses. In spite of its relevance, the precise dynamics of the photoinduced oxidation process as well as the reasons behind the dominant role of the competing CO photodesorption remain unclear. Here we use ab initio molecular dynamics with electronic friction that account for the highly excited and nonequilibrated system created by the laser to investigate both reactions. Our simulations successfully reproduce the main experimental findings: the existence of photoinduced oxidation and desorption, the large desorption to oxidation branching ratio, and the changes in the O K-edge X-ray absorption spectra attributed to the initial stage of the oxidation process. Now, we are able to monitor in detail the ultrafast CO desorption and CO oxidation occurring in the highly excited system and to disentangle what causes the unexpected inertness to the otherwise energetically favored oxidation.

Stereoinversion of tetrahedral p-block element hydrides.

The potential energy surfaces of 15 tetrahedral p-block element hydrides were screened on the multireference level. It was addressed whether stereoinversion competes against other reactions, such as reductive H2-elimination or hydride loss, and if so, along which pathway the stereomutation occurs. Importantly, stereoinversion transition structures for the ammonium cation (C4v) and the tetrahydridoborate anion (Cs) were identified for the first time. Revisiting methane's Cs symmetric inversion transition structure with the mHEAT+ protocol revealed an activation enthalpy for stereoinversion, in contrast to all earlier studies, which is 5 kJ mol-1 below the C-H bond dissociation enthalpy. Square planar structures were identified lowest in energy only for the inversion of AlH4 -, but a novel stepwise Cs-inversion was discovered for SiH4 or PH4 +. Overall, the present contribution delineates essentials of the potential energy surfaces of p-block element hydrides, while structure-energy relations offer design principles for the synthetically emerging field of structurally constrained compounds.

Dioxygen Activation and Pyrrole α-Cleavage with Calix[4]pyrrolato Aluminates: Enzyme Model by Structural Constraint.

The present work describes the reaction of triplet dioxygen with the porphyrinogenic calix[4]pyrrolato aluminates to alkylperoxido aluminates in high selectivity. Multiconfigurational quantum chemical computations disclose the mechanism for this spin-forbidden process. Despite a negligible spin-orbit coupling constant, the intersystem crossing (ISC) is facilitated by singlet and triplet state degeneracy and spin-vibronic coupling. The formed peroxides are stable toward external substrates but undergo an unprecedented oxidative pyrrole α-cleavage by ligand aromatization/dearomatization-initiated O-O σ-bond scission. A detailed comparison of the calix[4]pyrrolato aluminates with dioxygen-related enzymology provides insights into the ISC of metal- or cofactor-free enzymes. It substantiates the importance of structural constraint and element-ligand cooperativity for the functions of aerobic life.

PSIXAS: A Psi4 plugin for efficient simulations of X-ray absorption spectra based on the transition-potential and Δ-Kohn-Sham method.

Near edge X-ray absorption fine structure (NEXAFS) spectra and their pump-probe extension (PP-NEXAFS) offer insights into valence- and core-excited states. We present PSIXAS, a recent implementation for simulating NEXAFS and PP-NEXAFS spectra by means of the transition-potential and the Δ-Kohn-Sham method. The approach is implemented in form of a software plugin for the Psi4 code, which provides access to a wide selection of basis sets as well as density functionals. We briefly outline the theoretical foundation and the key aspects of the plugin. Then, we use the plugin to simulate PP-NEXAFS spectra of thymine, a system already investigated by others and us. It is found that larger, extended basis sets are needed to obtain more accurate absolute resonance positions. We further demonstrate that, in contrast to ordinary NEXAFS simulations, where the choice of the density functional plays a minor role for the shape of the spectrum, for PP-NEXAFS simulations the choice of the density functional is important. Especially hybrid functionals (which could not be used straightforwardly before to simulate PP-NEXAFS spectra) and their amount of "Hartree-Fock like" exact exchange affects relative resonance positions in the spectrum.

Iron doped gold cluster nanomagnets: ab initio determination of barriers for demagnetization.

Magnetic properties of small- and nano-sized iron doped gold clusters are calculated at the level of second order multireference perturbation theory. We first assess the methodology for small Au6Fe and Au7Fe clusters, which are representative of even and odd electron count systems. We find that larger active spaces are needed for the odd electron count system, Au7Fe, which exhibits isotropic magnetization behaviour. On the other hand, the even electron count system, Au6Fe, exhibits strong axial magnetic anisotropy. We then apply this methodology to the tetrahedral and truncated pyramidal nano-sized Au19Fe (with S = 3/2) and Au18Fe (with S = 2) clusters. We find that face substitutions result in the most stable structures, followed by edge and corner substitutions. However, for Au18Fe, corner substitution results in strong magnetic anisotropy and a large barrier for demagnetization while face substitution does not. Thus, although corner and face substituted Au18Fe have the same spin, only corner substituted Au18Fe can act as a single nanoparticle magnet.

An efficient first principles method for molecular pump-probe NEXAFS spectra: Application to thymine and azobenzene.

Pump-probe near edge X-ray absorption fine structure (PP-NEXAFS) spectra of molecules offer insight into valence-excited states, even if optically dark. In PP-NEXAFS spectroscopy, the molecule is "pumped" by UV or visible light enforcing a valence excitation, followed by an X-ray "probe" exciting core electrons into (now) partially empty valence orbitals. Calculations of PP-NEXAFS have so far been done by costly, correlated wavefunction methods which are not easily applicable to medium-sized or large molecules. Here we propose an efficient, first principles method based on density functional theory in combination with the transition potential and ΔSCF methodology (TP-DFT/ΔSCF) to compute molecular ground state and PP-NEXAFS spectra. We apply the method to n → π * pump/O-K-edge NEXAFS probe spectroscopy of thymine (for which both experimental and other theoretical data exist) and to n → π * or π → π * pump/N-K-edge NEXAFS probe spectroscopies of trans- and cis-azobenzene.

Control of Oxidation and Spin State in a Single-Molecule Junction.

The oxidation and spin state of a metal-organic molecule determine its chemical reactivity and magnetic properties. Here, we demonstrate the reversible control of the oxidation and spin state in a single Fe porphyrin molecule in the force field of the tip of a scanning tunneling microscope. Within the regimes of half-integer and integer spin state, we can further track the evolution of the magnetocrystalline anisotropy. Our experimental results are corroborated by density functional theory and wave function theory. This combined analysis allows us to draw a complete picture of the molecular states over a large range of intramolecular deformations.

The quest for best suited references for configuration interaction singles calculations of core excited states.

Near edge X-ray absorption fine structure (NEXAFS) simulations based on the conventional configuration interaction singles (CIS) lead to excitation energies, which are systematically blue shifted. Using a (restricted) open shell core hole reference instead of the Hartree Fock (HF) ground state orbitals improves (Decleva et al., Chem. Phys., 1992, 168, 51) excitation energies and the shape of the spectra significantly. In this work, we systematically vary the underlying SCF approaches, that is, based on HF or density functional theory, to identify best suited reference orbitals using a series of small test molecules. We compare the energies of the K edges and NEXAFS spectra to experimental data. The main improvement compared to conventional CIS, that is, using HF ground state orbitals, is due to the electrostatic influence of the core hole. Different SCF approaches, density functionals, or the use of fractional occupations lead only to comparably small changes. Furthermore, to account for bigger systems, we adapt the core-valence separation for our approach. We demonstrate that the good quality of the spectrum is not influenced by this approximation when used together with the non-separated ground state wave function. Simultaneously, the computational demands are reduced remarkably. © 2016 Wiley Periodicals, Inc.

Systematic Investigation into the Matsuda-Heck Reaction of α-Methylene Lactones: How Conformational Constraints Direct the ß-H-Elimination Step.

α-Methylene-γ-butyrolactone and α-methylene-δ-valerolactone undergo Pd-catalyzed Matsuda-Heck couplings with arene diazonium salts to α-benzyl butenolides or pentenolides, respectively, or to α-benzylidene lactones. The observed regioselectivity is strongly ring size dependent, with six-membered rings giving exclusively α-benzyl pentenolides, whereas the five-membered α-methylene lactone reacts to mixtures of regioisomers with a high proportion of (E)-α-benzylidene-γ-butyrolactones. DFT calculations suggest that the reasons for these differences are not thermodynamic but kinetic in nature. The relative energies of the conformers of the Pd σ-complexes resulting from insertion into the Pd-aryl bond were correlated with the dihedral angles between Pd and endo-ß-H. This correlation revealed that in the case of the six-membered lactone an energetically favorable conformer adopts a nearly synperiplanar Pd/endo-ß-H arrangement, whereas for the analogous Pd σ-complex of the five-membered lactone the smallest Pd/endo-ß-H dihedral angle is observed for a conformer with a comparatively high potential energy. The optimized conditions for Matsuda-Heck arylations of exo-methylene lactones were eventually applied to the synthesis of the natural product anemarcoumarin A.

A detailed assignment of NEXAFS resonances of imidazolium based ionic liquids.

In Near Edge X-Ray Absorption Fine Structure (NEXAFS) spectroscopy X-Ray photons are used to excite tightly bound core electrons to low-lying unoccupied orbitals of the system. This technique offers insight into the electronic structure of the system as well as useful structural information. In this work, we apply NEXAFS to two kinds of imidazolium based ionic liquids ([C(n)C1im](+)[NTf2](-) and [C4C1im](+)[I](-)). A combination of measurements and quantum chemical calculations of C K and N K NEXAFS resonances is presented. The simulations, based on the transition potential density functional theory method (TP-DFT), reproduce all characteristic features observed by the experiment. Furthermore, a detailed assignment of resonance features to excitation centers (carbon or nitrogen atoms) leads to a consistent interpretation of the spectra.

C K-edge NEXAFS spectra of graphene with physical and chemical defects: a study based on density functional theory.

Recently, C K-edge Near Edge X-ray Absorption Fine Structure (NEXAFS) spectra of graphite (HOPG) surfaces have been measured for the pristine material, and for HOPG treated with either bromine or krypton plasmas (Lippitz et al., Surf. Sci., 2013, 611, L1). Changes of the NEXAFS spectra characteristic for physical (krypton) and/or chemical/physical modifications of the surface (bromine) upon plasma treatment were observed. Their molecular origin, however, remained elusive. In this work we study by density functional theory, the effects of selected point and line defects as well as chemical modifications on NEXAFS carbon K-edge spectra of single graphene layers. For Br-treated surfaces, also Br 3d X-ray Photoelectron Spectra (XPS) are simulated by a cluster approach, to identify possible chemical modifications. We observe that some of the defects related to plasma treatment lead to characteristic changes of NEXAFS spectra, similar to those in experiment. Theory provides possible microscopic origins for these changes.