Interactions and reactivity in crystalline intermediates of mechanochemical cyclorhodation reactions.

There is experimental evidence that solid mixtures of the rhodium dimer [Cp*RhCl2]2 and benzo[h] quinoline (BHQ) produce two different polymorphic molecular cocrystals called 4α and 4ß under ball milling conditions. The addition of NaOAc to the mixture leads to the formation of the rhodacycle [Cp*Rh-(BHQ)Cl], where the central Rh atom retains its tetracoordinate character. Isolate 4ß reacts with NaOAc leading to the same rhodacycle while isolate 4α does not under the same conditions. We show that the puzzling difference in reactivity between the two cocrystals can be traced back to fundamental aspects of the intermolecular interactions between the BHQ and [Cp*RhCl2]2 fragments in the crystalline environment. To support this view, we report a number of descriptors of the nature and strength of chemical bonds and intermolecular interactions in the extended solids and in a cluster model. We calculate formal quantum mechanical descriptors based on electronic structure, electron density, and binding and interaction energies including an energy decomposition analysis. Without exception, all descriptors point to 4ß being a transient structure higher in energy than 4α with larger local and global electrophilic and nucleophilic powers, a more favorable spatial and energetic distribution of the frontier orbitals, and a more fragile crystal structure.

Water Maintains the UV-Vis Spectral Features During the Insertion of Anionic Naproxen and Ibuprofen into Model Cell Membranes.

UV-vis spectra of anionic ibuprofen and naproxen in a model lipid bilayer of the cell membrane are investigated using computational techniques in combination with a comparative analysis of drug spectra in purely aqueous environments. The simulations aim at elucidating the intricacies behind the negligible changes in the maximum absorption wavelength in the experimental spectra. A set of configurations of the systems constituted by lipid, water, and drugs or just water and drugs are obtained from classical Molecular Dynamics simulations. UV-vis spectra are computed in the framework of atomistic Quantum Mechanical/Molecular Mechanics (QM/MM) approaches together with Time-Dependent Density Functional Theory (TD-DFT). Our results suggest that the molecular orbitals involved in the electronic transitions are the same, regardless of the chemical environment. A thorough analysis of the contacts between the drug and water molecules reveals that no significant changes in UV-vis spectra are a consequence of ibuprofen and naproxen molecules being permanently microsolvated by water molecules, despite the presence of lipid molecules. Water molecules microsolvate the charged carboxylate group as expected but also microsolvate the aromatic regions of the drugs.

The transition state region in nonsynchronous concerted reactions.

The critical and vanishing points of the reaction force F(ξ) = -dV(ξ)/dξ yield five important coordinates (ξR, ξR* , ξTS, ξP* , ξP) along the intrinsic reaction coordinate (IRC) for a given concerted reaction or reaction step. These points partition the IRC into three well-defined regions, reactants (ξR→ξR* ), transition state (ξR* →ξP* ), and products (ξP* →ξP), with traditional roles of mostly structural changes associated with the reactants and products regions and mostly electronic activity associated with the transition state (TS) region. Following the evolution of chemical bonding along the IRC using formal descriptors of synchronicity, reaction electron flux, Wiberg bond orders, and their derivatives (or, more precisely, the intensity of the electron activity) unambiguously indicates that for nonsynchronous reactions, electron activity transcends the TS region and takes place well into the reactants and products regions. Under these circumstances, an extension of the TS region toward the reactants and products regions may occur.

Formation and evolution of C-C, C-O, C[double bond, length as m-dash]O and C-N bonds in chemical reactions of prebiotic interest.

A series of prebiotic chemical reactions yielding the precursor building blocks of amino acids, proteins and carbohydrates, starting solely from HCN and water is studied here. We closely follow the formation and evolution of the pivotal C-C, C-O, C[double bond, length as m-dash]O, and C-N bonds, which dictate the chemistry of the molecules of life. In many cases, formation of these bonds is set in motion by proton transfers in which individual water molecules act as catalysts so that water atoms end up in the products. Our results indicate that the prebiotic formation of carbon dioxide, formaldehyde, formic acid, formaldimine, glycolaldehyde, glycine, glycolonitrile, and oxazole derivatives, among others, are best described as highly nonsynchronous concerted single step processes. Nonetheless, for all reactions involving double proton transfer, the formation and breaking of O-H bonds around a particular O atom occur in a synchronous fashion, apparently independently from other primitive processes. For the most part, the first process to initiate seems to be the double proton transfer in the reactions where they are present, then bond breaking/formation around the reactive carbon in the carbonyl group and finally rupture of the C-N bonds in the appropriate cases, which are the most reluctant to break. Remarkably, within the limitations of our non-dynamical computational model, the wide ranges of temperature and pressure in which these reactions occur, downplay the problematic determination of the exact constraints on the early Earth.

Rationalizing the Substituent Effects in Diels-Alder Reactions of Triazolinediones with Anthracene.

In this work we tackle the problem of the substituent effects in the Diels-Alder cycloadditions between triazolinediones (TADs) and anthracene. Experiments showed that aryl TADs substituted with electron-withdrawing groups (EWG) are more reactive than those substituted with electron-donating (EDG) or alkyl groups. However, the molecular origin of this preference is not yet understood. By a combination of methods including the activation strain model (ASM), energy decomposition analysis (EDA), molecular orbital (MO) theory, and conceptual density functional theory (CDFT), we disclosed the substituent effects of TADs. First, ASM/EDA analysis revealed that the reactivity of alkyl and aryl-substituted TADs is controlled by interaction energies, ΔEint, which are ultimately defined by orbital interactions between frontier molecular orbitals. Moreover, alkyl-TADs are also controlled by the extent of strain at the transition state. The MO analysis suggested that the rate acceleration for EWG-substituted TADs is due to a more favorable orbital interaction between the HOMO of anthracene and the LUMO of the TADs, which is corroborated by calculations of charge transfer at the transition states. From CDFT, the chemical potential of anthracene is higher than those of TADs, indicating a flow of electron density from anthracene to TADs, in agreement with the results from the electrophilicity index.

Initial Recognition and Attachment of the Zika Virus to Host Cells: A Molecular Dynamics and Quantum Interaction Approach.

The zika virus (ZIKV), transmitted to humans from the bites of Aedes Aegypti and Aedes Albopictus mosquitoes produces Zika fever and neurodegenerative disorders that despite affecting millions of people, most recently in Africa and the Americas, has been declared a neglected tropical disease by the World Health Organization. In this work, atomistic molecular dynamics simulations followed by rigorous analysis of the intermolecular interactions reveal crucial aspects of the initial virus⋯cell molecular recognition and attachment, events that trigger the infectious cycle. Previous experimental studies have shown that Dermatan Sulfate (DS) and Chondroitin Sulfate A (CSA), two glycosaminoglycans which are actually epimers to each other and that are structural constituents of receptors expressed in cell membranes, are the preferred anchorage sites, with a marked preference for DS. Our calculations rationalize this preference from a molecular perspective as follows: when free of the virus, DS has one sulfate group that does not participate in intramolecular strong hydrogen bonds, thus, it is readily available to interact with the envelope protein of the virus (Zika-E), then, after formation of the complexes, Zika-E⋯DS exhibits ten strong salt brides connecting the two fragments against only six salt bridges and two hydrogen bonds in Zika-E⋯CSA. Our results complement the current view of the interaction between the virus and the receptor glycosoaminoglycans revealing that the negatively charged carboxylate groups in CSA and DS are just as important as the sulfates because of the formation of equally strong salt bridges with the positively charged Arginine and Lysine aminoacids in the envelope protein of the virus.

Analysis of Conformational Preferences in Caffeine.

High level DLPNO−CCSD(T) electronic structure calculations with extended basis sets over B3LYP−D3 optimized geometries indicate that the three methyl groups in caffeine overcome steric hindrance to adopt uncommon conformations, each one placing a C−H bond on the same plane of the aromatic system, leading to the C−H bonds eclipsing one carbonyl group, one heavily delocalized C−N bond constituent of the fused double ring aromatic system, and one C−H bond from the imidazole ring. Deletion of indiscriminate and selective non-Lewis orbitals unequivocally show that hyperconjugation in the form of a bidirectional −CH3 ⇆ aromatic system charge transfer is responsible for these puzzling conformations. The structural preferences in caffeine are exclusively determined by orbital interactions, ruling out electrostatics, induction, bond critical points, and density redistribution because the steric effect, the allylic effect, the Quantum Theory of Atoms in Molecules (QTAIM), and the non-covalent interactions (NCI), all predict wrong energetic orderings. Tiny rotational barriers, not exceeding 1.3 kcal/mol suggest that at room conditions, each methyl group either acts as a free rotor or adopts fluxional behavior, thus preventing accurate determination of their conformations. In this context, our results supersede current experimental ambiguity in the assignation of methyl conformation in caffeine and, more generally, in methylated xanthines and their derivatives.

Ring Vibrations to Sense Anionic Ibuprofen in Aqueous Solution as Revealed by Resonance Raman.

We unravel the potentialities of resonance Raman spectroscopy to detect ibuprofen in diluted aqueous solutions. In particular, we exploit a fully polarizable quantum mechanics/molecular mechanics (QM/MM) methodology based on fluctuating charges coupled to molecular dynamics (MD) in order to take into account the dynamical aspects of the solvation phenomenon. Our findings, which are discussed in light of a natural bond orbital (NBO) analysis, reveal that a selective enhancement of the Raman signal due to the normal mode associated with the C-C stretching in the ring, νC=C, can be achieved by properly tuning the incident wavelength, thus facilitating the recognition of ibuprofen in water samples.

The Role of Spike Protein Mutations in the Infectious Power of SARS-COV-2 Variants: A Molecular Interaction Perspective.

Specific S477N, N501Y, K417N, K417T, E484K mutations in the receptor binding domain (RBD) of the spike protein in the wild type SARS-COV-2 virus have resulted, among others, in the following variants: B.1.160 (20A or EU2, first reported in continental Europe), B1.1.7 (α or 20I501Y.V1, first reported in the United Kingdom), B.1.351 (ß or 20H/501Y.V2, first reported in South Africa), B.1.1.28.1 (γ or P.1 or 20J/501Y.V3, first reported in Brazil), and B.1.1.28.2 (ζ, or P.2 or 20B/S484K, also first reported in Brazil). From the analysis of a set of bonding descriptors firmly rooted in the formalism of quantum mechanics, including Natural Bond Orbitals (NBO), Quantum Theory of Atoms In Molecules (QTAIM) and highly correlated energies within the Domain Based Local Pair Natural Orbital Coupled Cluster Method (DLPNO-CCSD(T)), and from a set of computed electronic spectral patterns with environmental effects, we show that the new variants improve their ability to recognize available sites to either hydrogen bond or to form salt bridges with residues in the ACE2 receptor of the host cells. This results in significantly improved initial virus⋅⋅⋅cell molecular recognition and attachment at the microscopic level, which trigger the infectious cycle.

Thermodynamics and Intermolecular Interactions during the Insertion of Anionic Naproxen into Model Cell Membranes.

The insertion process of Naproxen into model dimyristoylphosphatidylcholine (DMPC) membranes is studied by resorting to state-of-the-art classical and quantum mechanical atomistic computational approaches. Molecular dynamics simulations indicate that anionic Naproxen finds an equilibrium position right at the polar/nonpolar interphase when the process takes place in aqueous environments. With respect to the reference aqueous phase, the insertion process faces a small energy barrier of ≈5 kJ mol-1 and yields a net stabilization of also ≈5 kJ mol-1. Entropy changes along the insertion path, mainly due to a growing number of realizable microstates because of structural reorganization, are the main factors driving the insertion. An attractive fluxional wall of noncovalent interactions is characterized by all-quantum descriptors of chemical bonding (natural bond orbitals, quantum theory of atoms in molecules, noncovalent interaction, density differences, and natural charges). This attractive wall originates in the accumulation of tiny transfers of electron densities to the interstitial region between the fragments from a multitude of individual intermolecular contacts stabilizing the tertiary drug/water/membrane system.

A molecular twist on hydrophobicity.

A thorough exploration of the molecular basis for hydrophobicity with a comprehensive set of theoretical tools and an extensive set of organic solvent S/water binary systems is discussed in this work. Without a single exception, regardless of the nature or structure of S, all quantum descriptors of bonding yield stabilizing S⋯water interactions, therefore, there is no evidence of repulsion and thus no reason for etymological hydrophobicity at the molecular level. Our results provide molecular insight behind the exclusion of S molecules by water, customarily invoked to explain phase separation and the formation of interfaces, in favor of a complex interplay between entropic, enthalpic, and dynamic factors. S⋯water interfaces are not just thin films separating the two phases; instead, they are non-isotropic regions with density gradients for each component whose macroscopic stability is provided by a large number of very weak dihydrogen contacts. We offer a definition of interface as the region in which the density of the components in the A/B binary system is not constant. At a fundamental level, our results contribute to better current understanding of hydrophobicity.

Binding of SARS-CoV-2 to Cell Receptors: A Tale of Molecular Evolution.

The magnified infectious power of the SARS-CoV-2 virus compared to its precursor SARS-CoV is intimately linked to an enhanced ability in the mutated virus to find available hydrogen-bond sites in the host cells. This characteristic is acquired during virus evolution because of the selective pressure exerted at the molecular level. We pinpoint the specific residue (in the virus) to residue (in the cell) contacts during the initial recognition and binding and show that the virus⋅⋅⋅cell interaction is mainly due to an extensive network of hydrogen bonds and to a large surface of noncovalent interactions. In addition to the formal quantum characterization of bonding interactions, computation of absorption spectra for the specific virus⋅⋅⋅cell interacting residues yields significant shifts of Δλmax =47 and 66 nm in the wavelength for maximum absorption in the complex with respect to the isolated host and virus, respectively.

A detailed look at the bonding interactions in the microsolvation of monoatomic cations.

Global and local descriptors of the properties of intermolecular bonding, formally derived from independent methodologies (QTAIM, NCI, NBO, density differences) afford a highly complex picture of the bonding interactions responsible for microsolvation of monoatomic cations. In all cases, the dominant factor dictating geometries and interaction strengths is the electrophilic power of the metal cation. The formal charge disrupts the hydrogen bonding network otherwise present in pristine water clusters, making the hydrogen bonds considerably stronger, even inducing some degree of covalency. All MO interactions are highly ionic, with strengths than in some cases approach that of the reference LiCl bond. Accumulation of electron density in the region connecting MO is observed, thus, ionic bonding in the microsolvation of monoatomic cations is not as simple as an electrostatic interaction between opposing charges.

Evolution of Bonding during the Insertion of Anionic Ibuprofen into Model Cell Membranes.

Descriptors of chemical bonding derived from five different analysis tools based on quantum mechanics (natural charges, electron density differences, atoms in molecules (AIM), natural bond orbitals (NBO), and non-covalent interactions (NCI) index) consistently afford a picture of a wall of weak, non-covalent intermolecular interactions separating anionic Ibuprofen from the environment. This wall, arising from the cumulative effect of a multitude of individual weak charge transfer interactions to the interstitial region between fragments, stabilizes the drug at all equilibrium positions in the free energy profile for its insertion into model cell membranes. The formal charge in anionic Ibuprofen strengthens all intermolecular interactions, having a particularly strong effect in the network of water to water hydrogen bonds in the solvent. Electron redistribution during the insertion process leads to a sensible reduction of electron delocalization in both the -CO2- group and the aromatic ring of Ibuprofen. Here, we conclusively show that, despite their purely classical origin, randomly chosen configurations from molecular dynamics simulations provide deep insight into the purely quantum nature of bonding interactions.

Entropy drives the insertion of ibuprofen into model membranes.

Understanding the migration of exogenous molecules to the interior of cell membranes is of pivotal importance to the design of new drugs and to the improvement of the capabilities of existing ones. This research dissects, from a molecular perspective, using classical molecular dynamics, the thermodynamic factors driving the insertion of ibuprofen into a model phosphatidylcholine membrane in an aqueous environment. We suggest an analysis of the insertion path that focuses on the net resulting force acting on the tertiary drug/water/membrane system; this allows us to understand the opposition that ibuprofen has to overcome as it inserts into the membrane. We provide conclusive evidence that entropy changes, arising from an increase of the number of possible microstates due to structural reorganization of the tertiary system, are the main factor driving this process. Our results allow us to unambiguously rationalize long standing conflicting experimental reports not understood up to now.