Exploring Caffeine–Phenol Interactions by the Inseparable Duet of Experimental and Theoretical Data

Intermolecular interactions are difficult to model, especially in systems formed by multiple interactions. Such is the case of caffeine–phenol. Structural data has been extracted by using mass-resolved excitation spectroscopy and double resonance techniques. Then the predictions of seven different computational methods have been explored to discover structural and energetic discrepancies between them that may even result in different assignments of the system. The results presented herein highlight the difficulty of constructing functionals to model systems with several competing interactions, and raise awareness of problems with assignments of complex systems with limited experimental information that rely exclusively on energetic data.     

Reconciling Electrostatic and n→π* Orbital Contributions in Carbonyl Interactions

Interactions between carbonyl groups are prevalent in protein structures. Earlier investigations identified dominant electrostatic dipolar interactions, while others implicated lone pair n→π* orbital delocalisation. Here these observations are reconciled. A combined experimental and computational approach confirmed the dominance of electrostatic interactions in a new series of synthetic molecular balances, while also highlighting the distance-dependent observation of inductive polarisation manifested by n→π* orbital delocalisation. Computational fiSAPT energy decomposition and natural bonding orbital analyses correlated with experimental data to reveal the contexts in which short-range inductive polarisation augment electrostatic dipolar interactions. Thus, we provide a framework for reconciling the context dependency of the dominance of electrostatic interactions and the occurrence of n→π* orbital delocalisation in C=O⋅⋅⋅C=O interactions.     

Halogen‐Bonding Interactions with π Systems: CCSD(T), MP2, and DFT Calculations

Halogen bonding is a noncovalent interaction between a halogen atom and a nucleophilic site. Interactions involving the π electrons of aromatic rings have received, up to now, little attention, despite the large number of systems in which they are present. We report binding energies of the interaction between either NCX or PhX (X=F, Cl, Br, I) and the aromatic benzene system as determined with the coupled cluster with perturbative triple excitations method [CCSD(T)] extrapolated at the complete basis set limit. Results are compared with those obtained by Møller–Plesset perturbation theory to second order (MP2) and density functional theory (DFT) calculations by using some of the most common functionals. Results show the important role of DFT in studying this interaction.     

Silver-Catalysed Enantioselective Addition of O?H and N?H Bonds to Allenes: A New Model for Stereoselectivity Based on Noncovalent Interactions

The ability of silver complexes to catalyse the enantioselective addition of O H and N H bonds to allenes is demonstrated for the first time by using optically active anionic ligands that were derived from oxophosphorus(V) acids as the sources of chirality. The intramolecular addition of acids, alcohols, and amines to allenes can be achieved with up to 73 % ee. The exploitation of a C H anomeric effect allowed the absolute configuration of a sample of 2-substituted tetrahydrofuran of low ee to be unambiguously assigned by comparison of the chiroptical ORD and VCD measurements with calculated spectra. In the second part of the work, the origin of the stereoselectivity was probed by DFT free-energy calculations of the transition states. A new model of enantiomeric differentiation was developed that was based on noncovalent interactions. This model allowed us to identify the source of stereoselectivity as weak attractive interactions; such dispersive forces are often overlooked in asymmetric catalysis. A new computational approach was developed that represents these interactions as colour-coded isosurfaces that are characterised by the reduced density-gradient profile.     

Amyloid Aggregates Arise from Amino Acid Condensations under Prebiotic Conditions

Current theories on the origin of life reveal significant gaps in our understanding of the mechanisms that allowed simple chemical precursors to coalesce into the complex polymers that are needed to sustain life. The volcanic gas carbonyl sulfide (COS) is known to catalyze the condensation of amino acids under aqueous conditions, but the reported di‐, tri‐, and tetra‐peptides are too short to support a regular tertiary structure. Here, we demonstrate that alanine and valine, two of the proteinogenic amino acids believed to have been among the most abundant on a prebiotic earth, can polymerize into peptides and subsequently assemble into ordered amyloid fibers comprising a cross‐β‐sheet quaternary structure following COS‐activated continuous polymerization of as little as 1 mm amino acid. Furthermore, this spontaneous assembly is not limited to pure amino acids, since mixtures of glycine, alanine, aspartate, and valine yield similar structures.     

Non‐enzymatic Ribonucleotide Reduction in the Prebiotic Context

Model studies of prebiotic chemistry have revealed compelling routes for the formation of the building blocks of proteins and RNA, but not DNA. Today, deoxynucleotides required for the construction of DNA are produced by reduction of nucleotides catalysed by ribonucleotide reductases, which are radical enzymes. This study considers potential non‐enzymatic routes via intermediate radicals for the ancient formation of deoxynucleotides. In this context, several mechanisms for ribonucleotide reduction, in a putative H₂S/HS^. environment, are characterized using computational chemistry. A bio‐inspired mechanistic cycle involving a keto intermediate and HSSH production is found to be potentially viable. An alternative pathway, proceeding through an enol intermediate is found to exhibit similar energetic requirements. Non‐cyclical pathways, in which HSS^. is generated in the final step instead of HS^., show a markedly increased thermodynamic driving force (ca. 70 kJ mol^?1) and thus warrant serious consideration in the context of the prebiotic ribonucleotide reduction.     

Protein–Nanoparticle Interaction‐Induced Changes in Protein Structure and Aggregation

Large surface area, small size, strong optical properties, controllable structural features, variety of bioconjugation chemistries, and biocompatibility make many different types of nanoparticles (NPs), such as gold NPs, useful for many biological applications, such as biosensing, cellular imaging, disease diagnostics, drug delivery, and therapeutics. Recently, interactions between proteins and NPs have been extensively studied to understand, control, and utilize the interactions involved in biomedical applications of NPs and several biological processes, such as protein aggregation, for many diseases, including Alzheimer's disease. These studies also offer fundamental knowledge on changes in protein structure, protein aggregation mechanisms, and ways to unravel the roles and fates of NPs within the human body. This review focuses on recent studies on the roles and uses of NPs in protein structural changes and aggregation processes.     

On the Prebiotic Synthesis of D‐Sugars Catalyzed by L‐Peptides: Assessments from First‐Principles Calculations

What accounts for a particular chiral selection in the case of a few sugars of prebiotic relevance, thereby mirroring the asymmetry observed in nature? By using first‐principles calculations, the generation of pentoses from glycolaldehyde (the initial product of the autocatalytic formose reaction), which has been detected in outer space), has been modeled by using L ‐Val‐L ‐Val as a primeval catalyst. Our theoretical study provides insight into the mechanism of this reaction and satisfactorily explains a few key molecular events. Our rationale agrees with the reported experimental data and shows that the D ‐configuration is only favored for ribose. L ‐pentoses are usually favored in the presence of L ‐configured dipeptides, as observed experimentally, although no chiral selection could be observed in the case of xylose. These results confirm that a prebiotic sugar soup could be fine‐tuned in the presence of shorter peptides as catalysts and that D ‐ribose would have also resulted in an advantageous imbalance for further amplification and chemical evolution.     

Characterization of a Multicomponent Lithium Lithiate from a Combined X‐Ray Diffraction,NMR Spectroscopy,and Computational Approach

An unusual lithium lithiate [Li(diglyme)₂][(diglyme)Li₂(C₄H₃S)₃], made up from three carbanions, two lithium cations, and a single donor base molecule in the anion and a single lithium cation, coordinated by two donor base molecules, is investigated in a combined study including X‐ray diffraction, NMR spectroscopy and computational approaches in solution and the solid state. While the multicomponent lithiate is the only species present in the solid state, solution NMR spectroscopy and computational methods were employed to identify a second species in solution. The dimer [(diglyme)Li(C₄H₃S)]₂ coexists with the lithiate in solution in a 1:1 ratio, the more the higher the polarity of the solvent is. Only the combination of this multitude of methods provides a firm picture of the whole.     

Are Heavy Pnictogen-π Interactions Really “π Interactions”?

The noncovalent interactions of heavy pnictogens with π-arenes play a fundamental role in fields like crystal engineering or catalysis. The strength of such bonds is based on an interplay between dispersion and donor/acceptor interactions, and is generally attributed to the presence of π-arenes. Computational studies of the interaction between the heavy pnictogens As, Sb and Bi and cyclohexane, in comparison with previous studies on the interaction between heavy pnictogens and benzene, show that this concept probably has to be revised. A thorough analysis of all the different energetic components that play a role in these systems, carried out with state-of-the-art computational methods, sheds light on how they influence one another and the effect that their interplay has on the overall system. Furthermore, the analysis of such interactions leads us to the unexpected finding that the presence of the pnictogen compounds strongly affects the conformational equilibrium of cyclohexane, reversing the relative stability of the chair and boat-twist conformers, and thus suggesting a possible application of tuneable dispersion energy donors to stabilise the desired conformation.