Quantitative model for rationalizing solvent effect in noncovalent CH-Aryl interactions.
Ontology highlight
ABSTRACT:
SUBMITTER: Emenike BU
PROVIDER: S-EPMC5975927 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The weak noncovalent interactions and flexibility of ligands play a key role in enantioselective metal-catalyzed reactions. In transition metal complexes and their catalytic applications, the experimental assessment and the design of key interactions is as difficult as the prediction of the enantioselectivities, especially for flexible, privileged ligands such as chiral phosphoramidites. Therefore, the interligand interactions in cis-PdII L2 Cl2 phosphoramidite complexes were investigated by NMR spectroscopy and computations. We were able to induce a strong conformational preference by breaking the symmetry of the C2 -symmetric side chain of one of the ligands, and shift the equilibrium between hetero- and homocomplexes towards heterocomplexes because of interligand interactions in the cis-complexes. The modulation of aryl substituents was exploited, along with the solvent effect. The combined CH-π and π-π interactions reveal design patterns for binding and folding of chiral ligands and catalysts.
| S-EPMC9298319 | biostudies-literature
Project description:Molecular structure does not easily identify the intricate noncovalent interactions that govern many areas of biology and chemistry, including design of new materials and drugs. We develop an approach to detect noncovalent interactions in real space, based on the electron density and its derivatives. Our approach reveals the underlying chemistry that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids. Most importantly, the method, requiring only knowledge of the atomic coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of nonbonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands.
| S-EPMC2864795 | biostudies-literature
Project description:Over the past decade, we have developed a spectroscopic approach to measure electric fields inside matter with high spatial (<1 Å) and field (<1 MV/cm) resolution. The approach hinges on exploiting a physical phenomenon known as the vibrational Stark effect (VSE), which ultimately provides a direct mapping between observed vibrational frequencies and electric fields. Therefore, the frequency of a vibrational probe encodes information about the local electric field in the vicinity around the probe. The VSE method has enabled us to understand in great detail the underlying physical nature of several important biomolecular phenomena, such as drug-receptor selectivity in tyrosine kinases, catalysis by the enzyme ketosteroid isomerase, and unidirectional electron transfer in the photosynthetic reaction center. Beyond these specific examples, the VSE has provided a conceptual foundation for how to model intermolecular (noncovalent) interactions in a quantitative, consistent, and general manner. The starting point for research in this area is to choose (or design) a vibrational probe to interrogate the particular system of interest. Vibrational probes are sometimes intrinsic to the system in question, but we have also devised ways to build them into the system (extrinsic probes), often with minimal perturbation. With modern instruments, vibrational frequencies can increasingly be recorded with very high spatial, temporal, and frequency resolution, affording electric field maps correspondingly resolved in space, time, and field magnitude. In this Account, we set out to explain the VSE in broad strokes to make its relevance accessible to chemists of all specialties. Our intention is not to provide an encyclopedic review of published work but rather to motivate the underlying framework of the methodology and to describe how we make and interpret the measurements. Using certain vibrational probes, benchmarked against computer models, it is possible to use the VSE to measure absolute electric fields in arbitrary environments. The VSE approach provides an organizing framework for thinking generally about intermolecular interactions in a quantitative way and may serve as a useful conceptual tool for molecular design.
| S-EPMC4667952 | biostudies-literature
Project description:The heterolytic decomposition of tert-butyl peroxyformate to tert-butanol and carbon dioxide, catalyzed by pyridine, is a long-known example of a reaction whose kinetics are strongly affected by solvent polarity. From DFT and ab initio methods together with the SMD implicit solvation model, an extension on the formerly accepted mechanism is proposed. This novel proposal involves the formation of a carbonic acid ester intermediate and its further decomposition, through an unreported pyridine-mediated stepwise route. Computed barriers for this mechanism at DLPNO/CCSD(T)-def2-TZVP are in excellent agreement with experimental kinetic data across different solvents. Furthermore, the strong relationships between activation energies, geometric parameters in the transition state and the characteristics of the different solvents are also analyzed in depth.
| S-EPMC8457178 | biostudies-literature
Project description:Carbohydrate-protein interactions play an important role in many molecular recognition processes. An exquisite combination of multiple factors favors the interaction of the receptor with one specific type of sugar, whereas others are excluded. Stacking CH-aromatic interactions within the binding site provide a relevant contribution to the stabilization of the resulting sugar-protein complex. Being experimentally difficult to detect and analyze, the key CH-π interaction features have been very often dissected using a variety of techniques and simple model systems. In the present work, diffusion NMR spectroscopy has been employed to separate the components of sugar mixtures in different solvents on the basis of their differential ability to interact through CH-π interactions with one particular aromatic cosolute in solution. The experimental data show that the properties of the solvent did also influence the diffusion behavior of the sugars present in the mixture, inhibiting or improving their separation. Overall, the results showed that, for the considered monosaccharide derivatives, their diffusion coefficient values and, consequently, their apparent molecular sizes and/or shapes depend on the balance between solute/cosolute as well as solute/solvent interactions. Thus, in certain media and in the presence of the aromatic cosolute, the studied saccharides that are more suited to display CH-π interactions exhibited a lower diffusion coefficient than the noncomplexing sugars in the mixture. However, when dissolved in another medium, the interaction with the solvent strongly competes with that of the aromatic cosolute.
| S-EPMC6641296 | biostudies-literature
Project description:Protein-small cosolute molecule interactions are ubiquitous and known to modulate the solubility, stability, and function of many proteins. Characterization of such transient weak interactions at atomic resolution remains challenging. In this work, we develop a simple and practical NMR method for extracting both energetic and dynamic information on protein-cosolute interactions from solvent paramagnetic relaxation enhancement (sPRE) measurements. Our procedure is based on an approximate (non-Lorentzian) spectral density that behaves exactly at both high and low frequencies. This spectral density contains two parameters, one global related to the translational diffusion coefficient of the paramagnetic cosolute, and the other residue specific. These parameters can be readily determined from sPRE data, and then used to calculate analytically a concentration normalized equilibrium average of the interspin distance, ⟨r-6⟩norm, and an effective correlation time, τC, that provide measures of the energetics and dynamics of the interaction at atomic resolution. We compare our approach with existing ones, and demonstrate the utility of our method using experimental 1H longitudinal and transverse sPRE data recorded on the protein ubiquitin in the presence of two different nitroxide radical cosolutes, at multiple static magnetic fields. The approach for analyzing sPRE data outlined here provides a powerful tool for deepening our understanding of extremely weak protein-cosolute interactions.
| S-EPMC7372007 | biostudies-literature
Project description:To investigate the effect of AHR deficiency on organoid differentiation or in stem cell state we performed RNA-seq of human colon organoids treated with CH-223191 or DMSO in stem cell conditions or during differentiation
2024-03-22 | GSE229116 | GEO
Project description:Alamethicin is a 20-amino acid antibiotic peptide that forms voltage-gated ion channels in lipid bilayers. Here we report calculations of its association free energy with membranes. The calculations take into account the various free-energy terms that contribute to the transfer of the peptide from the aqueous phase into bilayers of different widths. The electrostatic and nonpolar contributions to the solvation free energy are calculated using continuum solvent models. The contributions from the lipid perturbation and membrane deformation effects and the entropy loss associated with peptide immobilization in the bilayer are estimated from a statistical thermodynamic model. The calculations were carried out using two classes of experimentally observed conformations, both of which are helical: the NMR and the x-ray crystal structures. Our calculations show that alamethicin is unlikely to partition into bilayers in any of the NMR conformations because they have uncompensated backbone hydrogen bonds and their association with the membrane involves a large electrostatic solvation free energy penalty. In contrast, the x-ray conformations provide enough backbone hydrogen bonds for the peptide to associate with bilayers. We tested numerous transmembrane and surface orientations of the peptide in bilayers, and our calculations indicate that the most favorable orientation is transmembrane, where the peptide protrudes approximately 4 A into the water-membrane interface, in very good agreement with electron paramagnetic resonance and oriented circular dichroism measurements. The calculations were carried out using two alamethicin isoforms: one with glutamine and the other with glutamate in the 18th position. The calculations indicate that the two isoforms have similar membrane orientations and that their insertion into the membrane is likely to involve a 2-A deformation of the bilayer, again, in good agreement with experimental data. The implications of the results for the biological function of alamethicin and its capacity to oligomerize and form ion channels are discussed.
| S-EPMC1300662 | biostudies-other
Project description:Proline residues have unique roles in protein folding, structure, and function. Proline and the aromatic amino acids comprise the encoded cyclic protein residues. Aromatic protein side chains are defined by their negatively charged ? faces, while the faces of the proline ring are partially positively charged. This polarity results from their two-point connection of the side chain to the electron-withdrawing protein backbone, and the lower electronegativity of hydrogen compared to carbon, nitrogen, and oxygen. The hydrogens adjacent to the carbonyl and amide nitrogen, H? and H?, respectively, are the most partially positive. Proline's side chain is also conformationally restricted, allowing for interaction with aromatic residues with minimal entropic or steric penalty. Proline and aromatic residues can interact favorably with each other, due to both the hydrophobic effect and the interaction between the ? aromatic face and the polarized C-H bonds, called a CH/? interaction. Aromatic-proline interactions can occur locally, for example, to stabilize cis-amide bonds, and over larger distances, in the tertiary structures of proteins, and intermolecularly in protein-protein interactions. In peptides and proteins, aromatic-proline sequences more readily adopt cis-prolyl amide bonds, where the aromatic ring interacts with the proline ring in the cis conformation. In aromatic-proline sequences, Trp and Tyr are more likely to induce cis-amide bonds than Phe, suggesting an aromatic electronic effect. This result would be expected for a CH/? interaction, in which a more electron-rich aromatic would have a stronger (more cis-stabilizing) interaction with partial positive charges on prolyl hydrogens. In this Account, we describe our investigations into the nature of local aromatic-proline interactions, using peptide models. We synthesized a series of 26 peptides, TXPN, varying X from electron-rich to electron poor aromatic amino acids, and found that the population of cis-amide bond (Ktrans/cis) is tunable by aromatic electronics. With 4-substituted phenylalanines, we observed a Hammett correlation between aromatic electronics and Ktrans/cis, with cis-trans isomerism electronically controllable by 1.0 kcal/mol. All aromatic residues exhibit a higher cis population than Ala or cyclohexylalanine, with Trp showing the strongest aromatic-proline interaction. In addition, proline stereoelectronic effects can modulate cis-trans isomerism by an additional 1.0 kcal/mol. The aromatic-proline interaction is enthalpic, consistent with its description as a CH/? interaction. Proline-aromatic sequences can also promote cis-prolyl bonds, either through interactions of the aromatic ring with the preceding cis-proline or with the H? prior to cis-proline. Within proline-rich peptides, sequences commonly found in natively disordered proteins, aromatic residues promote multiple cis-amide bonds due to multiple favorable aromatic-proline interactions. Collectively, we found aromatic-proline interactions to be significantly CH/? in nature, tunable by aromatic electronics. We discuss these data in the context of aromatic-proline and aromatic-glycine interactions in local structure, in tertiary structure, in protein-protein interactions, and in protein assemblies.
| S-EPMC3780429 | biostudies-literature
Project description:Burgeoning interest in distal functionalization of aryl C-H bonds led to the development of iridium-catalyzed borylation reactions. The significance and inadequate mechanistic understanding of C(sp2)-H borylations motivated us to investigate the key catalytic steps and the origin of a directing-group-free regiocontrol in the reaction between aryl amides and B2pin2 (bis(pinacolato)diboron). An Ir(iii)(ubpy)tris(boryl) complex, generated from the pre-catalyst [Ir(OMe)(cod)]2 by the action of a bipyridine-urea ligand (ubpy) and B2pin2, is considered as the most likely active catalyst. The meta C-H activation of N,N-dihexylbenzamide is energetically more favorable over the para isomer. The origin of this preference is traced to the presence of a concerted action of noncovalent interactions (NCIs), primarily between the catalyst and the substrate, in the regiocontrolling transition states (TSs). Molecular insights into such TSs revealed that the N-H···O interaction between the tethered urea moiety of the Ir-bound ubpy ligand of the catalyst and the amide carbonyl of the substrate is a critical interaction that helps orient the meta C-H bond nearer to iridium. Other NCIs such as C-H···π between the substrate and the catalyst, C-H···O involving the substrate C-H and the oxygen of the B2pin2 ligand and C-H···N between the substrate and the N atom of the Ir-bound ubpy confirm the significance of such interactions in providing the desirable differential energies between the competing TSs that form the basis of the extent of regioselectivity.
| S-EPMC6457332 | biostudies-literature