Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment. METHODS: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual. FINDINGS: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group. INTERPRETATION: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. FUNDING: F Hoffmann-La Roche and Exelixis.

The value of virtual molecular tumor boards for informed clinical decision-making.

Genomic profiling and other new technologies have increased the volume and complexity of information available for guiding clinical decision-making in precision oncology. Consequently, there is a need for multidisciplinary expert teams, in the form of molecular tumor boards (MTBs), who can translate this information into a therapeutic plan, including matching patients to suitable clinical trials. Virtual MTBs (vMTBs) can help to overcome many of the challenges associated with in-person MTBs, such as limited time availability, access to appropriate experts or datasets, or interactions between institutions. However, real-world experience from vMTBs is lacking. Here, we describe oncologists' vMTB experiences and the value of working with multicenter and/or multinational vMTBs. We also address knowledge gaps and barriers that could affect the implementation of vMTBs in routine clinical practice. Case studies from Argentina, Turkey, and Portugal illustrate the value of informed clinical decision-making by vMTBs, including expansion of therapeutic options for patients, faster time to treatment, and the resulting improvement in patient outcomes or impact of vMTB discussions on patients. With the uptake of comprehensive genomic profiling and the evolution of some cancers now being conceptualized as a collection of rare diseases with small patient populations based on molecular profiling, the importance of MTBs has increased in modern cancer management. However, an adjustment in clinical decision-making by healthcare professionals is required and evidence of the added value of vMTBs is lacking. Existing vMTBs and recommendations from participating oncologists could point toward a structured evaluation and analysis of this new platform.

Calculation of the ELF in the excited state with single-determinant methods.

Since its first definition, back in 1990, the electron localization function (ELF) has settled as one of the most commonly employed techniques to characterize the nature of the chemical bond in real space. Although most of the work using the ELF has focused on the study of ground-state chemical reactivity, a growing interest has blossomed to apply these techniques to the nearly unexplored realm of excited states and photochemistry. Since accurate excited electronic states usually require to account appropriately for electron correlation, the standard single-determinant ELF formulation cannot be blindly applied to them, and it is necessary to turn to correlated ELF descriptions based on the two-particle density matrix (2-PDM). The latter requires costly wavefunction approaches, unaffordable for most of the systems of current photochemical interest. Here, we compare the exact, 2-PDM-based ELF results with those of approximate 2-PDM reconstructions taken from reduced density matrix functional theory. Our approach is put to the test in a wide variety of representative scenarios, such as those provided by the lowest-lying excited electronic states of simple diatomic and polyatomic molecules. Altogether, our results suggest that even approximate 2-PDMs are able to accurately reproduce, on a general basis, the topological and statistical features of the ELF scalar field, paving the way toward the application of cost-effective methodologies, such as time-dependent-Hartree-Fock or time-dependent density functional theory, in the accurate description of the chemical bonding in excited states of photochemical relevance.

Phaseolus vulgaris MIR1511 genotypic variations differentially regulate plant tolerance to aluminum toxicity.

The common-bean (Phaseolus vulgaris), a widely consumed legume, originated in Mesoamerica and expanded to South America, resulting in the development of two geographically distinct gene pools. Poor soil condition, including metal toxicity, are often constraints to common-bean crop production. Several P. vulgaris miRNAs, including miR1511, respond to metal toxicity. The MIR1511 gene sequence from the two P. vulgaris model sequenced genotypes revealed that, as opposed to BAT93 (Mesoamerican), the G19833 (Andean) accession displays a 58-bp deletion, comprising the mature and star miR1511 sequences. Genotyping-By-Sequencing data analysis from 87 non-admixed Phaseolus genotypes, comprising different Phaseolus species and P. vulgaris populations, revealed that all the P. vulgaris Andean genotypes and part of the Mesoamerican (MW1) genotypes analyzed displayed a truncated MIR1511 gene. The geographic origin of genotypes with a complete versus truncated MIR1511 showed a distinct distribution. The P. vulgaris ALS3 (Aluminum Sensitive Protein 3) gene, known to be important for aluminum detoxification in several plants, was experimentally validated as the miR1511 target. Roots from BAT93 plants showed decreased miR1511 and increased ALS3 transcript levels at early stages under aluminum toxicity (AlT), while G19833 plants, lacking mature miR1511, showed higher and earlier ALS3 response. Root architecture analyses evidenced higher tolerance of G19833 plants to AlT. However, G19833 plants engineered for miR1511 overexpression showed lower ALS3 transcript level and increased sensitivity to AlT. Absence of miR1511 in Andean genotypes, resulting in a diminished ALS3 transcript degradation, appears to be an evolutionary advantage to high Al levels in soils with increased drought conditions.

Partition of the electronic energy of the PM7 method via the interacting quantum atoms approach.

Partitions of the electronic energy such as that provided by the Interacting Quantum Atoms (IQA) approach have given valuable insights for numerous chemical systems and processes. Unfortunately, this kind of analysis may involve the integration of scalar fields over very irregular volumes, a condition which leads to a large and often prohibitive computational effort. These circumstances have limited the use of these energy partitions to systems comprising a few tens of atoms at most. On the other hand, semiempirical methods have proved useful in the study of systems of several thousands of atoms. Therefore, the goal of this work is to carry out partitions of the semiempirical method PM7 in compliance with the IQA approach. For this purpose, we computed one- and two-atomic energetic contributions whose sum equals the PM7 electronic energy. We illustrate how one might exploit the partition of electronic energies computed via the PM7 method by considering small organic and inorganic molecules and the energetics of individual hydrogen bond interactions within several water clusters which include (H2O)30, (H2O)50 and (H2O)100. We also considered the solvation of the amphiphilic caprylate anion to exemplify how to exploit the energy partition proposed in this paper. Overall, this investigation shows how the approach put forward herein might give further insights of the interactions occurring within complex systems in physical and biological chemistry.

NNAIMQ: A neural network model for predicting QTAIM charges.

Atomic charges provide crucial information about the electronic structure of a molecular system. Among the different definitions of these descriptors, the one proposed by the Quantum Theory of Atoms in Molecules (QTAIM) is particularly attractive given its invariance against orbital transformations although the computational cost associated with their calculation limits its applicability. Given that Machine Learning (ML) techniques have been shown to accelerate orders of magnitude the computation of a number of quantum mechanical observables, in this work, we take advantage of ML knowledge to develop an intuitive and fast neural network model (NNAIMQ) for the computation of QTAIM charges for C, H, O, and N atoms with high accuracy. Our model has been trained and tested using data from quantum chemical calculations in more than 45 000 molecular environments of the near-equilibrium CHON chemical space. The reliability and performance of NNAIMQ have been analyzed in a variety of scenarios, from equilibrium geometries to molecular dynamics simulations. Altogether, NNAIMQ yields remarkably small prediction errors, well below the 0.03 electron limit in the general case, while accelerating the calculation of QTAIM charges by several orders of magnitude.

A QCT View of the Interplay between Hydrogen Bonds and Aromaticity in Small CHON Derivatives.

The somewhat elusive concept of aromaticity plays an undeniable role in the chemical narrative, often being considered the principal cause of the unusual properties and stability exhibited by certain π skeletons. More recently, the concept of aromaticity has also been utilised to explain the modulation of the strength of non-covalent interactions (NCIs), such as hydrogen bonding (HB), paving the way towards the in silico prediction and design of tailor-made interacting systems. In this work, we try to shed light on this area by exploiting real space techniques, such as the Quantum Theory of Atoms in Molecules (QTAIM), the Interacting Quantum Atoms (IQA) approaches along with the electron delocalisation indicators Aromatic Fluctuation (FLU) and Multicenter (MCI) indices. The QTAIM and IQA methods have been proven capable of providing an unbiased and rigorous picture of NCIs in a wide variety of scenarios, whereas the FLU and MCI descriptors have been successfully exploited in the study of diverse aromatic and antiaromatic systems. We used a collection of simple archetypal examples of aromatic, non-aromatic and antiaromatic moieties within organic molecules to examine the changes in π delocalisation and aromaticity induced by the Aromaticity and Antiaromaticity Modulated Hydrogen Bonds (AMHB). We observed fundamental differences in the behaviour of systems containing the HB acceptor within and outside the ring, e.g., a destabilisation of the rings in the former as opposed to a stabilisation of the latter upon the formation of the corresponding molecular clusters. The results of this work provide a physically sound basis to rationalise the strengthening and weakening of AMHBs with respect to suitable non-cyclic non-aromatic references. We also found significant differences in the chemical bonding scenarios of aromatic and antiaromatic systems in the formation of AMHB. Altogether, our investigation provide novel, valuable insights about the complex mutual influence between hydrogen bonds and π systems.

Energetic Descriptors of Steric Hindrance in Real Space: An Improved IQA Picture*.

Steric hindrance (SH) plays a central role in the modern chemical narrative, lying at the core of chemical intuition. As it however happens with many successful chemical concepts, SH lacks an underlying physically sound root, and multiple mutually inconsistent approximations have been devised to relate this fuzzy concept to computationally derivable descriptors. We here argue that being SH related to spatial as well as energetic features of interacting systems, SH can be properly handled if we chose a real space energetic stance like the Interacting Quantum Atoms (IQA) approach. Drawing on previous work by Popelier and coworkers (ChemistryOpen 8, 560, 2019) we build an energetic estimator of SH, referred to as EST . We show that the rise in the self-energy of a fragment that accompanies steric congestion is a faithful proxy for the chemist's SH concept if we remove the effect of charge transfer. This can be done rigorously, and the EST here defined provides correct sterics even for hydrogen atoms, where the plain use of deformation energies leads to non-chemical results. The applicability of EST is validated in several chemical scenarios, going from atomic compressions to archetypal SN2 reactions. EST is shown to be a robust steric hindrance descriptor.

Interacting Quantum Atoms Analysis of the Reaction Force: A Tool to Analyze Driving and Retarding Forces in Chemical Reactions.

The analysis of the reaction force and its topology has provided a wide range of fruitful concepts in the theory of chemical reactivity over the years, allowing to identify chemically relevant regions along a reaction profile. The reaction force (RF), a projection of the Hellmann-Feynman forces acting on the nuclei of a molecular system onto a suitable reaction coordinate, is partitioned using the interacting quantum atoms approach (IQA). The exact IQA molecular energy decomposition is now shown to open a unique window to identify and quantify the chemical entities that drive or retard a chemical reaction. The RF/IQA coupling offers an extraordinarily detailed view of the type and number of elementary processes that take reactants into products, as tested on two sets of simple reactions.

Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients.

INTRODUCTION: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. METHODS: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3-5) infections in univariate and multivariable logistic regression models. RESULTS: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2-40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8-30.4) having a serious infection and 7 (6.3%; 95% CI 2.6-12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02-1.60; p = 0.03) as an independent risk factor for serious infection. CONCLUSION: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.

Management of Residual Disease After First-line Chemotherapy in a Patient With a Nonseminomatous Germ Cell Tumor.

The case An 18-year-old male presented with a one-month history of a nonpainful right testicular enlargement. He had no family history of neoplasia, nor any relevant past medical history. The physical examination was only remarkable for an enlarged right testicle. A testicular ultrasound revealed a 2.5-cm tumor, and serum tumor markers revealed an elevated ß-human chorionic gonadotropin (ß-HCG), 22 mUI/L (normal, < 0.06 mUI/L); elevated alpha-fetoprotein (AFP), 329 ng/mL (normal, 0-9 ng/mL); and normal lactate dehydrogenase (LDH), 135 /L (normal, 179 U/L). A right radical inguinal orchiectomy was performed. Pathological examination revealed a 2.4 cm by 2 cm embryonal carcinoma with tumor invasion into the tunica albuginea. Postsurgical tumor markers obtained 3 weeks after orchiectomy were ß-hCG, 100.5 mUI/L (normal, < 0.06 mUI/L); AFP, 1075 ng/mL (normal, 0-9 ng/mL); and LDH, 180 U/L (normal, 179 U/L). A chest, abdomen, and pelvis CT scan showed a 2.7-cm retroperitoneal lymph node enlargement, without visceral metastasis. Given the presence of node-positive disease with S2 serum markers, the diagnosis of a stage IIIB intermediate risk nonseminomatous germ cell tumor (NSGCT) was determined, and the patient underwent sperm banking. The patient was started on chemotherapy with 4 cycles of BEP (bleomycin, etoposide, and cisplatin), with a favorable tumor marker decline according to the Gustave-Roussy nomogram. After completion of the fourth chemotherapy cycle, serum tumor markers were negative, and 8 weeks after chemotherapy, the follow-up CT showed a 1.6-cm residual retroperitoneal lymph node conglomerate.

Lewis Structures from Open Quantum Systems Natural Orbitals: Real Space Adaptive Natural Density Partitioning.

Building chemical models from state-of-the-art electronic structure calculations is not an easy task, since the high-dimensional information contained in the wave function needs to be compressed and read in terms of the accepted chemical language. We have already shown ( Phys. Chem. Chem. Phys. 2018, 20, 21368) how to access Lewis structures from general wave functions in real space by reformulating the adaptive natural density partitioning (AdNDP) method proposed by Zubarev and Boldyrev ( Phys. Chem. Chem. Phys. 2008, 10, 5207). This provides intuitive Lewis descriptions from fully orbital invariant position space descriptors but depends on not immediately accessible higher order cumulant density matrices. By using an open quantum systems (OQS) perspective, we here show that the rigorously defined OQS fragment natural orbitals can be used to build a consistent real space adaptive natural density partitioning based only on spatial information and the system's one-particle density matrix. We show that this rs-AdNDP approach is a cheap, efficient, and robust technique that immerses electron counting arguments fully in the real space realm.

On the Relationship between Hydrogen Bond Strength and the Formation Energy in Resonance-Assisted Hydrogen Bonds.

Resonance-assisted hydrogen bonds (RAHB) are intramolecular contacts that are characterised by being particularly energetic. This fact is often attributed to the delocalisation of π electrons in the system. In the present article, we assess this thesis via the examination of the effect of electron-withdrawing and electron-donating groups, namely -F, -Cl, -Br, -CF3, -N(CH3)2, -OCH3, -NHCOCH3 on the strength of the RAHB in malondialdehyde by using the Quantum Theory of Atoms in Molecules (QTAIM) and the Interacting Quantum Atoms (IQA) analyses. We show that the influence of the investigated substituents on the strength of the investigated RAHBs depends largely on its position within the π skeleton. We also examine the relationship between the formation energy of the RAHB and the hydrogen bond interaction energy as defined by the IQA method of wave function analysis. We demonstrate that these substituents can have different effects on the formation and interaction energies, casting doubts regarding the use of different parameters as indicators of the RAHB formation energies. Finally, we also demonstrate how the energy density can offer an estimation of the IQA interaction energy, and therefore of the HB strength, at a reduced computational cost for these important interactions. We expected that the results reported herein will provide a valuable understanding in the assessment of the energetics of RAHB and other intramolecular interactions.

Laplacian of the Hamiltonian Kinetic Energy Density as an Indicator of Binding and Weak Interactions.

The kinetic energy is the center of a controversy between two opposite points of view about its role in the formation of a chemical bond. One school states that a lowering of the kinetic energy associated with electron delocalization is the key stabilization mechanism of covalent bonding. In contrast, the opposite school holds that a chemical bond is formed by a decrease in the potential energy due to a concentration of electron density within the binding region. In this work, a topographic analysis of the Hamiltonian Kinetic Energy Density (KED) and its laplacian is presented to gain more insight into the role of the kinetic energy within chemical interactions. This study is focused on atoms, diatomic and organic molecules, along with their dimers. In addition, it is shown that the laplacian of the Hamiltonian KED exhibits a shell structure in atoms and that their outermost shell merge when a molecule is formed. A covalent bond is characterized by a concentration of kinetic energy, potential energy and electron densities along the internuclear axis, whereas a charge-shift bond is characterized by a fusion of external concentration shells and a depletion in the bonding region. In the case of weak intermolecular interactions, the external shell of the molecules merge into each other resulting in an intermolecular surface comparable to that obtained by the Non-covalent interaction (NCI) analysis.

Directing the Crystal Packing in Triphenylphosphine Gold(I) Thiolates by Ligand Fluorination.

We explore herein the supramolecular interactions that control the crystalline packing in a series of fluorothiolate triphenylphosphine gold(I) compounds with the general formula [Au(SRF)(Ph3P)] in which Ph3P = triphenylphosphine and SRF = SC6F5, SC6HF4-4, SC6F4(CF3)-4, SC6H3F2-2,4, SC6H3F2-3,4, SC6H3F2-3,5, SC6H4(CF3)-2, SC6H4F-2, SC6H4F-3, SC6H4F-4, SCF3, and SCH2CF3. We use for this purpose (i) DFT electronic structure calculations and (ii) the quantum theory of atoms in molecules and the non-covalent interactions index methods of wave function analyses. Our combined experimental and computational approach yields a general understanding of the effects of ligand fluorination in the crystalline self-assembly of the examined systems, in particular, about the relative force of aurophilic contacts compared with other supramolecular interactions. We expect this information to be useful in the design of materials based on gold coordination compounds.

Posta las lilas: A model of integral commitment to the community.

Background: The Posta Sanitaria Las Lilas (La Posta) is a health promotion project of the medical school. Its purpose is to improve the health of individuals and the society by fostering qualitative changes in people's attitudes and habits in relation to every aspect of their health. The project serves a population of 25,000 inhabitants that live in conditions of vulnerability and poverty. It is based on a specific approach to social commitment and accountability that integrates teaching, research, and care with the whole community. Activities: The project activities are oriented toward key dimensions for each person and the community. There are two programs: health and education that involve physicians, students, residents, teachers, volunteers, and community members. Outcomes: The project has increased the number of medical appointments, medical records, and workshop participants. It is difficult to establish objective indicators that may reflect the changes in the life of the community members. In this article, findings of an impact evaluation study are presented. We also describe unexpected results for those who participated in the project. Conclusion: La Posta is part of the University's agenda and a place of meaningful and formative learning. All program activities are implemented with the support and resources of the institution. A network of various organizations cooperates with La Posta in order to help promote the welfare of the community. They are all committed to contributing to the development of project participants' personal resources rather than merely addressing their unmet needs. This requires thinking about people in all dimensions (biological, psychological, social, and spiritual).

On Electrostatics, Covalency, and Chemical Dashes: Physical Interactions versus Chemical Bonds.

The increasing availability of real-space interaction energies between quantum atoms or fragments that provide a chemically intuitive decomposition of intrinsic bond energies into electrostatic and covalent terms [see, for instance, Chem. Eur. J. 2018, 24, 9101] provides evidence for differences between the physicist's concept of interaction and the chemist's concept of a bond. Herein, it is argued that, for the former, all types of interactions are treated equally, whereas, for the latter, only the covalent short-range interactions have actually been used to build intuition about chemical graphs and chemical bonds. This has led to the bonding role of long-range Coulombic terms in molecular chemistry being overlooked. Simultaneously, blind consideration of electrostatic terms in chemical bonding parlance may lead to confusion. The relationship between these concepts is examined herein, and some notes of caution on how to merge them are proposed.

Exotic Bonding Regimes Uncovered in Excited States.

Real-space tools were employed to show that the chemical bonding scenario used routinely to understand ground states lacks the necessary flexibility in excited states. It is shown that, even for two-center, two-electron bonds, the real-space bond orders have exotic values that have never been reported. The nature of these situations was uncovered by using electron-counting techniques that provide an appealing statistical interpretation of bonding descriptors, together with simple physical models. Bond orders greater than one as well as negative bond orders for a single bonding electron pair emerge in situations in which the electrons in the pair show a gregarious (bosonic) instead of the usual lonely (fermionic) behavior. In the first case the gregarious pair is intra-atomic, whereas the coupling is interatomic in the second. A number of examples are used to substantiate these claims.

Chemical Bonding from the Statistics of the Electron Distribution.

An introduction to the theory of chemical bonding from the point of view of the statistics of the electron distribution is presented. When atoms bind to form a molecule, their originally fixed number of electrons ceases to be a well-defined observable, and this implies that their in-the-molecule electron populations fluctuate. If a chemically meaningful definition of an atom in a molecule is assumed, the probabilities of finding a given number of electrons in each of the atoms comprising the molecule can be computed. We show in this review how the complete electron distribution function (EDF) can be used to reconstruct the basic concepts and quantities used in chemical bonding without recourse to the orbital paradigm. From the statistical point of view, which inherits Born's probabilistic interpretation of quantum mechanics, a set of atoms are bonded when their electron populations are mutually dependent. We quantify this statistical dependence by the cumulant moments of the EDF, which provide a consistent description of both two- and multi-center bonding. Particular attention is paid to building EDFs from model wavefunctions. With this, a simple bridge with orbital thinking is built. The statistical interpretation allows to easily classify all possible bonds of a given kind. We show that there are vast unexplored territories that should receive due consideration. Although building EDFs from models is easy and very instructive, the contrary is considerably more difficult. Recipes to extract chemical information from computed EDFs are also reviewed and, in all the cases, simple toy systems are used to show how the methodology works, allowing non-experts to follow easily the presentation.

Tetrel Interactions from an Interacting Quantum Atoms Perspective.

Tetrel bonds, the purportedly non-covalent interaction between a molecule that contains an atom of group 14 and an anion or (more generally) an atom or molecule with lone electron pairs, are under intense scrutiny. In this work, we perform an interacting quantum atoms (IQA) analysis of several simple complexes formed between an electrophilic fragment (A) (CH3F, CH4, CO2, CS2, SiO2, SiH3F, SiH4, GeH3F, GeO2, and GeH4) and an electron-pair-rich system (B) (NCH, NCO-, OCN-, F-, Br-, CN-, CO, CS, Kr, NC-, NH3, OC, OH2, SH-, and N3-) at the aug-cc-pvtz coupled cluster singles and doubles (CCSD) level of calculation. The binding energy ( E bind AB ) is separated into intrafragment and inter-fragment components, and the latter in turn split into classical and covalent contributions. It is shown that the three terms are important in determining E bind AB , with absolute values that increase in passing from electrophilic fragments containing C, Ge, and Si. The degree of covalency between A and B is measured through the real space bond order known as the delocalization index ( δ AB ). Finally, a good linear correlation is found between δ AB and E xc AB , the exchange correlation (xc) or covalent contribution to E bind AB .