Importance of Orbital Optimization for Double-Hybrid Density Functionals: Application of the OO-PBE-QIDH Model for Closed- and Open-Shell Systems

We assess here the reliability of orbital optimization for modern double-hybrid density functionals such as the parameter-free PBE-QIDH model. We select for that purpose a set of closed- and open-shell strongly and weakly bound systems, including some standard and widely used data sets, to show that orbital optimization improves the results with respect to standard models, notably for electronically complicated systems, and through first-order properties obtained as derivatives of the energy.This work is supported by the “Ministerio de Economía y Competitividad” of Spain and the “European Regional Development Fund” through project CTQ2014-55073-P

Quadratic integrand double-hybrid made spin-component-scaled

We propose two analytical expressions aiming to rationalize the spin-component-scaled (SCS) and spin-opposite-scaled (SOS) schemes for double-hybrid exchange-correlation density-functionals. Their performances are extensively tested within the framework of the nonempirical quadratic integrand double-hybrid (QIDH) model on energetic properties included into the very large GMTKN30 benchmark database, and on structural properties of semirigid medium-sized organic compounds. The SOS variant is revealed as a less computationally demanding alternative to reach the accuracy of the original QIDH model without losing any theoretical background.A.J.P.J. and J.C.S.G. thank the “Ministerio de Economía y Competitividad” of Spain and the “European Regional Development Fund” through Project No. CTQ2014-55073-P for financial support

Speed-Up of the Excited-State Benchmarking: Double-Hybrid Density Functionals as Test Cases

The EX6-0, EX7-0, and EX7-1 representative benchmark sets are developed for the fast evaluation of the performance of a density functional, or more generally of a computational protocol, in modeling low-lying valence singlet–singlet excitation energies of organic dyes within the range of 1.5 to 4.5 eV. All sets share the advantage of being small (a maximum of 7 molecules) but providing statistical errors representative of larger and extended databases. To that extent, the EX7-1 benchmark set goes a step further and is composed of systems as small as possible in order to alleviate the associated computational cost. The reliability of all the sets is assessed through the benchmarking of 15 modern double-hybrid density functionals. The investigation shows not only that the 3 benchmark sets provide close error metrics for each density functional but also that when taking advantage of the Resolution-of-the-Identity and a balanced triple-ζ basis set (e.g., def2-TZVP), double hybrids overperform the “popular” hybrids in modeling vertical absorption, emission, and adiabatic energies.A.J.P.J. and J.C.S.G. thank the “Ministerio de Economía y Competitividad” of Spain and the “European Regional Development Fund” through the project CTQ2014-55073-P for financial support

Range-Separated Double-Hybrid Functional from Nonempirical Constraints

On the basis of our previous developments in the field of nonempirical double hybrids, we present here a new exchange-correlation functional based on a range-separated model for the exchange part and integrating a nonlocal perturbative correction to the electron correlation contribution. Named RSX-QIDH, the functional is free from any kind of empirical parametrization. Its range-separation parameter is set to recover the total energy of the hydrogen atom, thus eliminating the self-interaction error for this one-electron system. Subsequent tests on some relevant benchmark data sets confirm that the self-interaction error is particularly low for RSX-QIDH. This new functional provides also correct dissociation profiles for charged rare-gas dimers and very accurate ionization potentials directly from Kohn–Sham orbital energies. Above all, these good results are not obtained at the expense of other properties. Indeed, further tests on standard benchmarks show that RSX-QIDH is competitive with the more empirical ωB97X-2 double hybrid and outperforms the parent LC-PBE long-range corrected hybrid, thus underlining the important role of the nonlocal perturbative correlation.E.B. gratefully acknowledges the GENCI-CINES for HPC resources (Projects AP010810360 and A0040810359)

Partnering dispersion corrections with modern parameter-free double-hybrid density functionals

The PBE-QIDH and SOS1-PBE-QIDH double-hybrid density functionals are merged with a pair of dispersion corrections, namely the pairwise additive D3(BJ) and the non-local correlation functional VV10, leading to the corresponding dispersion-corrected models. The parameters adjusting each of the dispersion corrections to the functionals are obtained by fitting to well-established energy datasets (e.g. S130) used as a benchmark, giving rise to functionals spanning covalent and non-covalent binding forces. The application of the models to challenging systems out of the training set, like those comprising the L7 database of large supramolecular complexes, or the S66x8 dataset of stretched and elongated intermolecular distances, reveals the high accuracy of the coupling.JCSG and AJPJ thank the “Ministerio de Economía y Competitividad” of Spain and the “European Regional Development Fund” through project CTQ2014-55073-P

Benchmarking Density Functionals on Structural Parameters of Small-/Medium-Sized Organic Molecules

In this Letter we report the error analysis of 59 exchange-correlation functionals in evaluating the structural parameters of small- and medium-sized organic molecules. From this analysis, recently developed double hybrids, such as xDH-PBE0, emerge as the most reliable methods, while global hybrids confirm their robustness in reproducing molecular structures. Notably the M06-L density functional is the only semilocal method reaching an accuracy comparable to hybrids’. A comparison with errors obtained on energetic databases (including thermochemistry, reaction barriers, and interaction energies) indicate that most of the functionals have a coherent behavior, showing low (or high) deviations on both energy and structure data sets. Only a few of them are more prone toward one of these two properties.A.J.P.-J. and J.C.S.-G. thank the “Ministerio de Economía y Competitividad” of Spain and the “European Regional Development Fund” through Project CTQ2014-55073-P for financial and computational support. X.X. thanks the National Natural Science Foundation of China (Grants 91427301 and 21133004) and the Ministry of Science and Technology (Grant 2013CB834606)

Controlled tautomeric switching in azonaphthols tuned by substituents on the phenyl ring

A series of new tautomeric azonaphthols are synthesized and the possibilities for molecular switching are investigated using molecular spectroscopy, X-ray analysis and density functional theory quantum chemical calculations. Two opposite effects that influence switching are studied: attaching a piperidine sidearm, and adding substituents to the phenyl ring. On the one hand, the attached piperidine moiety stabilizes the enol form leading to a controlled shift of the equilibrium upon protonation. On the other hand, the relative stability of the azonaphthol tautomers strongly depends on the effects of the substituents on the phenyl ring: electron donors tend to stabilize the enol tautomer, whereas electron acceptors lead to stabilization of the keto form. However, these effects do not shift fully the equilibrium towards either of the tautomers. Nevertheless, the effect of the substituents can be an additional tool to affect the switching between “on” and “off” states. Electron-withdrawing substituents stabilize the keto form and impede switching to the off state, whereas electron donors stabilize the enol form. The effect of the piperidine unit is dominant overall, and with strongly electron-withdrawing substituents at the phenyl ring, the enol form exists as a zwitterion

Hypertension, type 2 diabetes, obesity, and p53 mutations negatively correlate with metastatic colorectal cancer patients’ survival

IntroductionWe studied the predictive and prognostic influences of hypertension (HT), type 2 diabetes (T2D), weight, and p53 mutations in metastatic colorectal cancer (CRC) patients.Patients and methodsT2D was diagnosed according to the ADA criteria. HT was classified according to the ACC/AHA guidelines. BMI (body-mass index) was calculated and classified according to the WHO criteria. TruSigt™Oncology 500 kit was applied to construct the genomic libraries for Next Generation Sequencing (NGS) analysis. The Illumina NovaSeq 6000 technological platform and the Illumina TruSight Oncology 500 bioinformatics pipeline were applied to analyze results. Overall survival (OS) was calculated through Kaplan-Meier curves. Univariate and multivariate analyses were performed to assess the relationships between clinical and/or molecular covariates. Associations between HT, T2D, BMI, p53, and clinical variables were evaluated by the χ2 test. P < 0.05 were considered statistically significant.ResultsTwo-hundred-forty-four patients were enrolled. One-hundred-twenty (49.2%), 110 (45.1%), and 50 (20.5%) patients were affected by overweight, HT, and T2D, respectively. DC (disease control) was achieved more frequently in patients without T2D (83.1%) compared to the diabetic ones (16.9%) (P = 0.0246). DC, KRAS mutational status, T2D, BMI, and concomitant presence of T2D, BMI, and HT associated with survival (P < 0.05). At multivariate analysis, age (≥65 vs. <65 years), response to first-line chemotherapy (DC vs. no DC), and concomitant presence of T2D, BMI, and HT (HR: 4.56; 95% CI: 2.40–8.67; P = 0.0217) emerged as independent prognostic variables. P53 was mutated in 31/53 analyzed cases (60.4%). The most frequent gene variants were p.Arg175His and p.Cys135Tyr. High BMI (>25 kg/m2) associated with occurrence of p53 mutations (P < 0.0001). P53 mutated patients presented a worse prognosis compared to the wild-type ones (HR: 3.21; 95% CI: 1.43–7.23; P = 0.0047).ConclusionDiabetic, hypertensive and overweight metastatic CRC patients are a negative prognostic subgroup deserving specific therapeutic strategies. P53 mutations associate with prognosis and BMI unrevealing complex and unexplored connections between metabolism and cancer occurrence

Congenital myopathies: Clinical phenotypes and new diagnostic tools

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis

Charge and Proton Transfer Reactions: Insights from Theory

Photochemistry is a science concerned with structures and dynamical processes resulting from the interaction of the light with molecules. The understanding of molecular processes triggered by the electronic excitation relies on a proper chemical-physical characterization based on a sound theoretical modeling of the photophysics and the photochemistry. From the more strict point of view of the theoretical chemistry, computational methods provide nowadays a powerful tool to analyze and single out structural, electronic, and environmental factors affecting molecular systems. In the present thesis, we developed and validated methods based on time-dependent density functional theory (TD-DFT) to simulate and analyze in detail processes activated by the electronic excitation and operating in optically allowed excited states. An extensive number of examples regarding important classes of processes has been taken into account, including photo-reactivity (excited state proton transfer, proton coupled electron transfer, photo-activated ring opening), photophysics (fluorescence quenching, radiative and non radiative decay processes). In each case, a computational protocol has been built up by focusing on the following steps: 1) validation of the TD-DFT functionals to calculate excited state electronic energies and gradients and, as a consequence, to obtain transition energies involved in the molecular absorption and emission, and to obtain minimum energy structures, transition states, and reaction paths on the excited state Potential Energy Surface, respectively; 2) analysis of photophysical processes (absorption, emission) and of photoreactivity (mechanism) in terms of the influence of bulk solvent, specific interactions with solvent molecules, nature of reactants, concentration of reactants; 3) development of new ad hoc designed parameters, obtained from the electronic density, to effectively accounts for and, as a consequence, to effectively predict charge transfer-driven processes such as photo-reactions and the interconversion between electronic states. Several pilot systems have been considered, chosen as important and/or popular examples of the corresponding photo-induced event under study, and more specifically 1) the proton coupled electron transfer triggered upon irradiation along an oligo-peptide in aqueous solution; 2) the excited proton transfer between the coumarine photo-acid and a base molecule in toluene solution; 3) the fluorescence signatures, including a photo-induced electron transfer as the possible quenching event in commercial rhodamine derivatives; and 4) the complex decay routes coupled to the photo-induced ring opening in a spyropiran molecule. Very promising results have been obtained, in terms both of validation of the developed protocols and of the capability to interpret and support experimental results. Many of them, in particular those concerning effective density-based parameters, opened a new scenario for future progresses in the theoretical-computational photo-chemistry