Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system.

In multicellular organisms, duplicated genes can diverge through tissue-specific gene expression patterns, as exemplified by highly regulated expression of RUNX transcription factor paralogs with apparent functional redundancy. Here we asked what cell-type-specific biologies might be supported by the selective expression of RUNX paralogs during Langerhans cell and inducible regulatory T cell differentiation. We uncovered functional nonequivalence between RUNX paralogs. Selective expression of native paralogs allowed integration of transcription factor activity with extrinsic signals, while non-native paralogs enforced differentiation even in the absence of exogenous inducers. DNA binding affinity was controlled by divergent amino acids within the otherwise highly conserved RUNT domain and evolutionary reconstruction suggested convergence of RUNT domain residues toward submaximal strength. Hence, the selective expression of gene duplicates in specialized cell types can synergize with the acquisition of functional differences to enable appropriate gene expression, lineage choice and differentiation in the mammalian immune system.

On the performance of HRPA(D) for NMR spin-spin coupling constants: Smaller molecules, aromatic and fluoroaromatic compounds.

In this study, the performance of the doubles-corrected higher random-phase approximation [HRPA(D)] has been investigated in calculations of nuclear magnetic resonance spin-spin coupling constants (SSCCs) for 58 molecules with the experimental values used as the reference values. HRPA(D) is an approximation to the second-order polarization propagator approximation (SOPPA) and is, therefore, computationally less expensive than SOPPA. HRPA(D) performs comparable and sometimes even better than SOPPA, and therefore, when calculating SSCCs, it should be considered as an alternative to SOPPA. Furthermore, it was investigated whether a coupled-cluster singles, doubles and perturbative triples [CCSD(T)] or Møller-Plesset second order (MP2) geometry optimization was optimal for a SOPPA and a HRPA(D) SSCC calculation for eight smaller molecules. CCSD(T) is the optimal geometry optimization for the SOPPA calculation, and MP2 was optimal for HRPA(D) SSCC calculations.

Performance of range-separated long-range SOPPA short-range density functional theory method for vertical excitation energies.

In this paper, benchmark results are presented on the calculation of vertical electronic excitation energies using a long-range second-order polarization propagator approximation (SOPPA) description with a short-range density functional theory description based on the Perdew-Burke-Ernzerhof (PBE) functional. The excitation energies are investigated for 132 singlet states and 71 triplet states across 28 medium-sized organic molecules. The results show that overall SOPPA-srPBE always performs better than PBE and that SOPPA-srPBE performs better than SOPPA for singlet states, but slightly worse than SOPPA for triplet states when CC3 results are the reference values.

The variational quantum eigensolver self-consistent field method within a polarizable embedded framework.

We formulate and implement the Variational Quantum Eigensolver Self Consistent Field (VQE-SCF) algorithm in combination with polarizable embedding (PE), thereby extending PE to the regime of quantum computing. We test the resulting algorithm, PE-VQE-SCF, on quantum simulators and demonstrate that the computational stress on the quantum device is only slightly increased in terms of gate counts compared to regular VQE-SCF. On the other hand, no increase in shot noise was observed. We illustrate how PE-VQE-SCF may lead to the modeling of real chemical systems using a simulation of the reaction barrier of the Diels-Alder reaction between furan and ethene as an example.

On the geometry dependence of the nuclear magnetic resonance chemical shift of mercury in thiolate complexes: A relativistic density functional theory study.

Thiolate containing mercury(II) complexes of the general formula [Hg(SR) n $$ {}_n $$ ] 2 - n $$ {}^{2-n} $$ have been of great interest since the toxicity of mercury was recognized. 199Hg nuclear magnetic resonance spectroscopy (NMR) is a powerful tool for characterization of mercury complexes. In this work, the Hg shielding constants in a series of [Hg(SR) n $$ {}_n $$ ] 2 - n $$ {}^{2-n} $$ complexes are therefore investigated computationally with particular emphasis on their geometry dependence. Geometry optimizations and NMR chemical shift calculations are performed at the density functional theory (DFT) level with both the zeroth-order regular approximation (ZORA) and four-component relativistic methods. The four exchange-correlation (XC) functionals PBE0, PBE, B3LYP, and BLYP are used in combination with either Dyall's Gaussian-type (GTO) or Slater-type orbitals (STOs) basis sets. Comparing ZORA and four-component calculations, one observes that the calculated shielding constants for a given molecular geometry have a constant difference of ∼ $$ \sim $$ 1070 ppm. This confirms that ZORA is an acceptable relativistic method to compute NMR chemical shifts. The combinations of four-component/PBE0/v3z and ZORA/PBE0/QZ4P are applied to explore the geometry dependence of the isotropic shielding. For a given coordination number, the distance between mercury and sulfur is the key factor affecting the shielding constant, while changes in bond and dihedral angles and even different side groups have relatively little impact.

The Importance of Anharmonicity and Solvent Effects on the OH Radical Attack on Nucleobases.

Previous theoretical investigations of the reactions between an OH radical and a nucleobase have stated the most important pathways to be the C5-C6 addition for pyrimidines and the C8 addition for purines. Furthermore, the abstraction of a methyl hydrogen from thymine has also been proven an important pathway. The conclusions were based solely on gas-phase calculations and harmonic vibrational frequencies. In this paper, we supplement the calculations by applying solvent corrections through the polarizable continuum model (PCM) solvent model and applying anharmonicity in order to determine the importance of anharmonicity and solvent effects. Density functional theory (DFT) at the ωB97-D/6-311++G(2df,2pd) level with the Eckart tunneling correction is used. The total reaction rate constants are found to be 1.48 ×10-13 cm3 molecules-1s-1 for adenine, 1.02 ×10-11 cm3 molecules-1s-1 for guanine, 5.52 ×10-13 cm3 molecules-1s-1 for thymine, 1.47 ×10-13 cm3 molecules-1s-1 for cytosine and 7.59 ×10-14 cm3 molecules-1s-1 for uracil. These rates are found to be approximately two orders of magnitude larger than experimental values. We find that the tendencies observed for preferred pathways for reactions calculated in a solvent are comparable to the preferred pathways for reactions calculated in gas phase. We conclude that applying a solvent has a larger impact on more parameters compared to the inclusion of anharmonicity. For some reactions the inclusion of anharmonicity has no effect, whereas for others it does impact the energetics.

Cohesins functionally associate with CTCF on mammalian chromosome arms.

Cohesins mediate sister chromatid cohesion, which is essential for chromosome segregation and postreplicative DNA repair. In addition, cohesins appear to regulate gene expression and enhancer-promoter interactions. These noncanonical functions remained unexplained because knowledge of cohesin-binding sites and functional interactors in metazoans was lacking. We show that the distribution of cohesins on mammalian chromosome arms is not driven by transcriptional activity, in contrast to S. cerevisiae. Instead, mammalian cohesins occupy a subset of DNase I hypersensitive sites, many of which contain sequence motifs resembling the consensus for CTCF, a DNA-binding protein with enhancer blocking function and boundary-element activity. We find cohesins at most CTCF sites and show that CTCF is required for cohesin localization to these sites. Recruitment by CTCF suggests a rationale for noncanonical cohesin functions and, because CTCF binding is sensitive to DNA methylation, allows cohesin positioning to integrate DNA sequence and epigenetic state.

Calculation of electric field gradients in Cd(II) model complexes of the CueR protein metal site.

With this work we first test various DFT functionals against CCSD(T) for calculation of EFGs at the position of Cd(II) in a very small model system, Cd(SCH3)2. Moreover, the available basis sets in ADF are tested in terms of basis set convergence, and the effect of including relativistic effects using the scalar relativistic and spin orbit ZORA Hamiltonians is explored. The results indicate that an error of up to around 10% on the calculated EFG may be expected using spin-orbit ZORA and the BHandHLYP functional with a locally dense basis set. Next, this method was applied to model systems of the CueR protein, aiming to interpret 111Ag-PAC spectroscopic data. Note that 111Ag decays to 111Cd on which the PAC data are recorded. Surprisingly, model systems truncated - as is often done - at the first C-C bond from the central Cd(II) are inadequate in size, and larger model systems must be employed to achieve reliable EFG calculations. The calculated EFGs agree well with experimental PAC data, and indicate that shortly after the nuclear decay the structure relaxes from linear two-coordinate AgS2 in the native protein, to a structure (or structures) where Cd(II) recruits additional ligands such as backbone carbonyl oxygens to achieve higher coordination number(s).

Indirect nuclear spin-spin couplings with third-order contributions added to the SOPPA method.

In this article, a modification of the second-order polarization propagator approximation (SOPPA) method is introduced and illustrated for the calculation of the indirect nuclear spin-spin couplings. The standard SOPPA method, although cheaper in terms of computational cost, offers less accurate results than the ones obtained with coupled cluster methods. A new method, named SOPPA+A3-3, was therefore developed by adding the terms of the third-order A matrix that rely on the second-order double amplitudes. The performance of this third-order contribution was studied using the coupled cluster singles and doubles method as a reference, calculating the spin-spin couplings of molecules of diverse sizes and compositions, and comparing them to the SOPPA method. The results show that inclusion of this third-order contribution gives more accurate results than the standard SOPPA method with a level of accuracy close to that of the coupled cluster method with only a small increase in the computational cost of the response calculation that dominates the computational cost for small- to medium-sized molecules. The implementation of the first contributions to the third-order polarization propagator approximation in the Dalton program, thus, already shows a significant change in these molecular properties over those obtained with the standard SOPPA method.

A Theoretical Study of Hydrogen Abstraction Reactions in Guanosine and Uridine.

All practically possible hydrogen abstraction reactions for guanosine and uridine have been investigated through quantum chemical calculations of energy barriers and rate constants. This was done at the level of density functional theory (DFT) with the ωB97X-D functional and the 6-311++G(2df,2pd) Pople basis set. Transition state theory with the Eckart tunneling correction was used to calculate the rate constants. The results show that the reaction involving the hydrogen labelled C4' in the ribofuranose part has the largest rate constant for guanosine with the value 5.097×1010 L mol-1s-1 and the largest for uridine with the value 1.62×1010 L mol-1s-1. Based on the results for these two nucleosides, there is a noticeable similarity between the rate constants in the ribofuranose part of the molecule, even though they are bound to two entirely different nucleobases.

A Combined Experimental and Theoretical Study of ESR Hyperfine Coupling Constants for N,N,N',N'-Tetrasubstituted p-Phenylenediamine Radical Cations.

A test set of N,N,N',N'-tetrasubstituted p-phenylenediamines are experimentally explored using ESR (electron spin resonance) spectroscopy and analysed from a computational standpoint thereafter. This computational study aims to further aid structural characterisation by comparing experimental ESR hyperfine coupling constants (hfccs) with computed values calculated using ESR-optimised "J-style" basis sets (6-31G(d,p)-J, 6-31G(d,p)-J, 6-311++G(d,p)-J, pcJ-1, pcJ-2 and cc-pVTZ-J) and hybrid-DFT functionals (B3LYP, PBE0, TPSSh, ωB97XD) as well as MP2. PBE0/6-31g(d,p)-J with a polarised continuum solvation model (PCM) correlated best with the experiment, giving an R2 value of 0.8926. A total of 98% of couplings were deemed satisfactory, with five couplings observed as outlier results, thus degrading correlation values significantly. A higher-level electronic structure method, namely MP2, was sought to improve outlier couplings, but only a minority of couples showed improvement, whilst the remaining majority of couplings were negatively degraded.

A tale of two vectors: A Lanczos algorithm for calculating RPA mean excitation energies.

The experimental and theoretical determination of the mean excitation energy, I(0), and the stopping power, S(v), of a material is of great interest in particle and material physics and radiation therapy. For calculations of I(0), the complete set of electronic transitions in a given basis set is required, effectively limiting such calculations to systems with a small number of electrons, even at the random-phase approximation (RPA)/time-dependent Hartree-Fock (TDHF) or time-dependent density-functional theory level. To overcome such limitations, we present here the implementation of a Lanczos algorithm adapted for the paired RPA/TDHF eigenvalue problem in the Dalton program and show that it provides good approximation of the entire RPA eigenspectra in a reduced space. We observe rapid convergence of I(0) with the number of Lanczos vectors as the algorithm favors the transitions with large contributions. In most cases, the algorithm recovers RPA I(0) values of up to 0.5% accuracy at less than a quarter of the full space size. The algorithm not only exploits the RPA paired structure to save computational resources but also preserves certain sum-over-states properties, as first demonstrated by Johnson et al. [Comput. Phys. Commun. 120, 155 (1999)]. The block Lanczos RPA solver, as presented here, thus shows promise for computing mean excitation energies for systems larger than what was computationally feasible before.

Magnesium(II)-ATP Complexes in 1-Ethyl-3-Methylimidazolium Acetate Solutions Characterized by 31 Mg ß-Radiation-Detected NMR Spectroscopy.

The complexation of MgII with adenosine 5'-triphosphate (ATP) is omnipresent in biochemical energy conversion, but is difficult to interrogate directly. Here we use the spin- 1/2 ß-emitter 31 Mg to study MgII -ATP complexation in 1-ethyl-3-methylimidazolium acetate (EMIM-Ac) solutions using ß-radiation-detected nuclear magnetic resonance (ß-NMR). We demonstrate that (nuclear) spin-polarized 31 Mg, following ion-implantation from an accelerator beamline into EMIM-Ac, binds to ATP within its radioactive lifetime before depolarizing. The evolution of the spectra with solute concentration indicates that the implanted 31 Mg initially bind to the solvent acetate anions, whereafter they undergo dynamic exchange and form either a mono- (31 Mg-ATP) or di-nuclear (31 MgMg-ATP) complex. The chemical shift of 31 Mg-ATP is observed up-field of 31 MgMg-ATP, in accord with quantum chemical calculations. These observations constitute a crucial advance towards using ß-NMR to probe chemistry and biochemistry in solution.

The best density functional theory functional for the prediction of 1 H and 13 C chemical shifts of protonated alkylpyrroles.

The prediction of 13 C chemical shifts can be challenging with density functional theory (DFT). In this study 39 different functionals and three different basis sets were tested on three neutral alkylpyrroles and their corresponding protonated species. The calculated shielding constants were compared to experimental data and results from previous calculations at the MP2. We find that the meta-hybrid functional TPSSh with either the Pople style basis set 6-311++G(2d,p) or the polarization consistent basis set pcSseg-1 gives the best results for the 13 C chemical shifts, whereas for the 1 H chemical shifts it is the TPSSh functional with either the 6-311++G(2d,p) or pcSseg-2 basis set. Including an explicit solvent molecule hydrogen bonded to NH in the alkylpyrroles improves the results slightly for the 13 C chemical shifts. On the other hand, for 1 H chemical shifts the opposite is true. Compared to calculations at the MP2 level none of the DFT functionals can compete with MP2 for the 13 C chemical shifts but for the 1 H chemical shifts the investigated DFT functionals are shown to give better agreement with experiment than MP2 calculations.

Free Molecule Studies by Perturbed γ-γ Angular Correlation: A New Path to Accurate Nuclear Quadrupole Moments.

Accurate nuclear quadrupole moment values are essential as benchmarks for nuclear structure models and for the interpretation of experimentally determined nuclear quadrupole interactions in terms of electronic and molecular structure. Here, we present a novel route to such data by combining perturbed γ-γ angular correlation measurements on free small linear molecules, realized for the first time within this work, with state-of-the-art ab initio electronic structure calculations of the electric field gradient at the probe site. This approach, also feasible for a series of other cases, is applied to Hg and Cd halides, resulting in Q(^{199}Hg,5/2^{-})=+0.674(17) b and Q(^{111}Cd,5/2^{+})=+0.664(7) b.

A Density Functional Theory Study of Optical Rotation in Some Aziridine and Oxirane Derivatives.

We present time-dependent density functional theory (TDDFT) calculations of the electronic optical rotation (ORP) for seven oxirane and two aziridine derivatives in the gas phase and in solution and compare the results with the available experimental values. For seven of the studied molecules it is the first time that their optical rotation was studied theoretically and we have therefore investigated the influence of several settings in the TDDFT calculations on the results. This includes the choice of the one-electron basis set, the exchange-correlation functional or the particular polarizable continuum model (PCM). We can confirm that polarized quadruple zeta basis sets augmented with diffuse functions are necessary for converged results and find that the aug-pc-3 basis set is a viable alternative to the frequently employed aug-cc-pVQZ basis set. Based on our study, we cannot recommend the generalized gradient functional KT3 for calculations of the ORP in these compounds, whereas the hybrid functional PBE0 gives results quite similar to the long-range correct CAM-B3LYP functional. Finally, we observe large differences in the solvent effects predicted by the integral equation formalism of PCM and the SMD variant of PCM. For the majority of solute/solvent combinations in this study, we find that the SMD model in combination with the PBE0 functional and the aug-pc-3 basis set gives the best agreement with the experimental values.

Prediction of the standard potentials for one-electron oxidation of N,N,N',N' tetrasubstituted p-phenylenediamines by calculation.

The formal potentials for the reversible one-electron oxidation of N,N,N',N' tetrasubstituted p-phenylenediamines in acetonitrile have been applied as a test set for benchmarking computational methods for a series of compounds with only small structural differences. The aim of the study is to propose a simple method for calculating the standard oxidation potentials, and therefore, the protocol is progressively developed by adding more terms in the energy expression. In addition, the effect of including implicit solvation models (IEFPCM, CPCM, and SMD), larger basis sets, and correlation methods are investigated. The oxidation potentials calculated using the G3MP2B3 approach with IEFPCM resulted in the best fit (R2 = 0.9624), but the slope of the correlation line, 0.74, is far from the optimal value, 1.00. B3LYP/6-311++G(d,p) and TPSSh/6-311++G(2d,p) yielded only slightly less consistent data (R2 = 0.9388 and R2 = 0.9425), but with much better slopes, 1.00 and 0.94, respectively. We conclude that it is important to investigate the basis set size and treatment of electron correlation when calculating oxidation potentials for N,N,N',N' tetrasubstituted p-phenylenediamines.

Benchmarking Correlated Methods for Static and Dynamic Polarizabilities: The T145 Data Set Evaluated with RPA, RPA(D), HRPA, HRPA(D), SOPPA, SOPPA(CC2), SOPPA(CCSD), CC2, and CCSD.

Due to the importance of predicting static and dynamic polarizabilities, the performance of various correlated linear response methods including random phase approximation (RPA), RPA(D), higher-order random phase approximation (HRPA), HRPA(D), second-order polarization propagator approximation (SOPPA), SOPPA(CC2), SOPPA(CCSD), CC2, and CCSD has been evaluated against CCSD(T) (static case) and CCSD (dynamic cases) for the T145 set of 145 organic molecules. The benchmark reveals that the HRPA(D) method has the best performance for both static and dynamic polarizabilities apart from CCSD. RPA(D) ranks second for the dynamic cases and third for the static case. Using coupled-cluster amplitudes in SOPPA(CCSD) and SOPPA(CC2), the SOPPA results are significantly improved. The HRPA method has the largest deviations from the reference values for both cases. In general, according to the performance and computational cost of the methods, the HRPA(D) and RPA(D) methods are proposed for calculations of static and dynamic polarizabilities of this and similar sets of molecules.

The aug-cc-pVTZ-J basis set for the p-block fourth-row elements Ga, Ge, As, Se, and Br.

The aug-cc-pVTZ-J basis set family is extended to include the fourth-row p-block elements Ga, Ge, As, Se, and Br. We use the established approach outlined by Sauer and coworkers (J. Chem. Phys. 115, 1324 [2001], J. Chem. Phys. 133, 054308 [2010], J. Chem. Theory Comput. 7, 4070 [2011], and J. Chem. Theory Comput. 7, 4077 [2011]) where the completely uncontracted aug-cc-pVTZ basis set is saturated with tight s-, p-, d-, and f-functions to form the aug-cc-pVTZ-Juc basis set for the tested elements. The saturation is carried out on the simplest hydrides possible for the tested elements GaH, GeH4 , AsH3 , H2 Se, and HBr until an improvement is less than 0.01% for all s-, p-, and d-functions added. f-Functions are added to an improvement less than or equal to 1.0% due to the computational expense these functions add. The saturated aug-cc-pVTZ-Juc (26s16p12d5f) is then recontracted using the molecular orbital coefficients from self-consistent field calculations on the simple hydrides to improve computational efficiency. During contraction of the basis set, we observe that the linear hydrogen bromide molecule has a slower convergence than the other tested molecules which sets a limit on the accuracy obtained. All calculations with the contracted aug-cc-pVTZ-J [17s10p7d5f] gives results that are within 1.0% of the uncontracted results at considerable computational savings.

Azo-hydrazone molecular switches: Synthesis and NMR conformational investigation.

A series of five intramolecularly hydrogen-bonded arylhydrazone (aryl = phenol, p-nitrophenol, anisole, quinoline) derived molecular switches have been synthesized and characterized by NMR and HRMS techniques. It was found that the compounds exist as different isomers in solution. An investigation of both conformational and/or configurational changes of the azo-hydrazone compounds was carried out by 1D 1 H- and 13 C- spectra, 2D NOESY, COSY, HSQC, and HMBC techniques. It was found that these stimuli-responsive molecular switches exist mainly in the E form by intramolecularly hydrogen bonded between NH and the pyridine nitrogen at equilibrium. Deprotonation of the neutral E form yields the E' deprotonated isomer. Prediction of 13 C-NMR chemical shifts was achieved by DFT quantum mechanical calculations. Anions have traditionally been difficult to calculate correctly, so calculations of the anion using different functionals, basis sets, and solvent effects are also included. Deuterium isotope effects on the 13 C-NMR chemical shifts were employed in the assignments and furthermore utilized as indicators of intramolecular hydrogen bonding. Studies in various organic solvents including CDCl3 , CD3 CN, and DMSO-d6 were also performed aiming to monitor dynamic changes over several days. The effect of the hydrogen bonded solvents leads to Z forms.