Showing papers on "Conformational isomerism published in 2023"
TL;DR: In this paper , a new computational setup rooted in quantum-chemical computations of increasing accuracy guided by machine learning tools is proposed to validate a new set of representative amino acids (glycine, alanine, serine, cysteine, threonine, aspartic acid and asparagine).
Abstract: The accurate characterization of prototypical bricks of life can strongly benefit from the integration of high resolution spectroscopy and quantum mechanical computations. We have selected a number of representative amino acids (glycine, alanine, serine, cysteine, threonine, aspartic acid and asparagine) to validate a new computational setup rooted in quantum-chemical computations of increasing accuracy guided by machine learning tools. Together with low-lying energy minima, the barriers ruling their interconversion are evaluated in order to unravel possible fast relaxation paths. Vibrational and thermal effects are also included in order to estimate relative free energies at the temperature of interest in the experiment. The spectroscopic parameters of all the most stable conformers predicted by this computational strategy, which do not have low-energy relaxation paths available, closely match those of the species detected in microwave experiments. Together with their intrinsic interest, these accurate results represent ideal benchmarks for more approximate methods.
6 citations
TL;DR: In this article , a single RNA sequence was shown to fold into conformationally and architecturally heterogeneous structures under near-physiological solution conditions, and the authors provided direct visual evidence that the sequence-structure relationship of RNA under physiologically relevant solution conditions is more complex than the one-to-one relationship for well-structured proteins.
Abstract: RNA flexibility is reflected in its heterogeneous conformation. Through direct visualization using atomic force microscopy (AFM) and the adenosylcobalamin riboswitch aptamer domain as an example, we show that a single RNA sequence folds into conformationally and architecturally heterogeneous structures under near-physiological solution conditions. Recapitulated 3D topological structures from AFM molecular surfaces reveal that all conformers share the same secondary structural elements. Only a population-weighted cohort, not any single conformer, including the crystal structure, can account for the ensemble behaviors observed by small-angle X-ray scattering (SAXS). All conformers except one are functionally active in terms of ligand binding. Our findings provide direct visual evidence that the sequence-structure relationship of RNA under physiologically relevant solution conditions is more complex than the one-to-one relationship for well-structured proteins. The direct visualization of conformational and architectural ensembles at the single-molecule level in solution may suggest new approaches to RNA structural analyses.
5 citations
TL;DR: A combined experimental and theoretical study has been carried out on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid as mentioned in this paper , which led to the identification of 13 stable low-energy minima.
Abstract: A combined experimental and theoretical study has been carried out on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group significantly increases the conformational complexity with respect to the parent amino acid threonine. The conformational landscape has been characterized in great detail, with special attention given to the inter-conversion pathways between different conformers. This led to the identification of 13 stable low-energy minima. The equilibrium population of so many conformers produces a very complicated and congested rotational spectrum that could be assigned through a strategy that combines several levels of quantum chemical calculations with the principles of machine learning. Twelve conformers out of 13 could be experimentally characterized. The results obtained from the analysis of the intra-molecular interactions can be exploited to accurately model fluorine-substitution effects in biomolecules.
4 citations
TL;DR: In this article , the one-pot synthesis of benzo[1,2-a:3,4-a':5,6-a'']triazulene (BTA) was reported, wherein three azulene units were embedded through a tandem reaction comprising of two steps involving Suzuki coupling and Knoevenagel condensation between a readily available triborylated truxene precursor and 8-bromo-1-naphthaldehyde.
Abstract: We report here the one-pot synthesis of benzo[1,2-a:3,4-a':5,6-a'']triazulene (BTA), wherein three azulene units are embedded through a tandem reaction comprising of two steps involving Suzuki coupling and Knoevenagel condensation between a readily available triborylated truxene precursor and 8-bromo-1-naphthaldehyde. Its nitration leads to a regioselective trinitrated product, namely, BTA-NO2. Single-crystal X-ray crystallography revealed that the superstructure of BTA consists of a dimer stacked by two enantiomeric helicene conformers, while that of BTA-NO2 consists of an unprecedented p-tetramer stacked from two enantiomeric dimers, that is, four distinct helicene conformers. Both compounds show excellent stability and fluorescence with large Stokes shifts of up to 174 nm. In addition, BTA-NO2 exhibits unique solvatochromic effect in different solvents and hydrogen bonding-induced emission transfer in different ratios of THF/H2O solutions.
3 citations
TL;DR: In this article , a one-layer MIM method with trimer fragments (MIM1trimer) is proposed for the prediction of NMR chemical shifts of large nucleic acids using their MIM fragment-based quantum chemical approach.
Abstract: We have developed, implemented, and assessed an efficient protocol for the prediction of NMR chemical shifts of large nucleic acids using our molecules-in-molecules (MIM) fragment-based quantum chemical approach. To assess the performance of our approach, MIM-NMR calculations are calibrated on a test set of three nucleic acids, where the structure is derived from solution-phase NMR studies. For DNA systems with multiple conformers, the one-layer MIM method with trimer fragments (MIM1trimer) is benchmarked to get the lowest energy structure, with an average error of only 0.80 kcal/mol with respect to unfragmented full molecule calculations. The MIMI-NMRdimer calibration with respect to unfragmented full molecule calculations shows a mean absolute deviation (MAD) of 0.06 and 0.11 ppm, respectively, for 1H and 13C nuclei, but the performance with respect to experimental NMR chemical shifts is comparable to the more expensive MIM1-NMR and MIM2-NMR methods with trimer subsystems. To compare with the experimental chemical shifts, a standard protocol is derived using DNA systems with Protein Data Bank (PDB) IDs 1SY8, 1K2K, and 1KR8. The effect of structural minimizations is employed using a hybrid mechanics/semiempirical approach and used for computations in solution with implicit and explicit-implicit solvation models in our MIM1-NMRdimer methodology. To demonstrate the applicability of our protocol, we tested it on seven nucleic acids, including structures with nonstandard residues, heteroatom substitutions (F and B atoms), and side chain mutations with a size ranging from ∼300 to 1100 atoms. The major improvement for predicted MIM1-NMRdimer calculations is obtained from structural minimizations and implicit solvation effects. A significant improvement with the explicit-implicit solvation model is observed only for two smaller nucleic acid systems (1KR8 and 7NBK), where the expensive first solvation shell is replaced by the microsolvation model, in which a single water molecule is added for each solvent-exposed amino and imino protons, along with the implicit solvation. Overall, our target accuracy of ∼0.2-0.3 ppm for 1H and ∼2-3 ppm for 13C has been achieved for large nucleic acids. The proposed MIM-NMR approach is accurate and cost-effective (linear scaling with system size), and it can aid in the structural assignments of a wide range of complex biomolecules.
3 citations
TL;DR: In this article , the conformer-rotamer ensemble sampling tool (CREST) was used to perform extensive conformational searches of four different steroid hormone molecules, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepsiandresterone acetate (AcO-DHEa), in deuterated dimethyl sulfoxide and some also in carbon tetrachloride.
Abstract: Steroid hormone molecules may exhibit very different functionalities based on the associated functional groups and their 3D arrangements in space, i.e., absolute configurations and conformations. Infrared (IR) and vibrational circular dichroism (VCD) spectra of four different steroid hormones, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepiandrosterone acetate (AcO-DHEA), were measured in deuterated dimethyl sulfoxide and some also in carbon tetrachloride. Extensive conformational searches were carried out using the recent developed conformer-rotamer ensemble sampling tool (CREST) which also accounts for solvent effects using an implicit solvation model. All the CREST conformational candidates were then reoptimized at the B3LYP-D3BJ/def2-TZVPD with the PCM of solvent. The good agreements between the experimental IR and VCD spectra and the theoretical simulations provide a conclusive information about their conformational distribution and absolute configurations. The experimental and theoretical IR and VCD spectra of AcO-DHEA in the carbonyl and alkene stretching region showed some discrepancies, and the possible causes related to solvent effects, large amplitude motions and levels of theory used in the modelling were explored in detail. As part of the investigation, additional calculations at the B3LYP-D3BJ/6-31++G (2d,p) and B3LYP-D3BJ/cc-pVTZ levels, as well as some ‘mixed’ calculations with the double-hybrid functional B2PLYP-D3 were also carried out. The results indicate that the double-hybrid functional is important for predicting the correct IR band pattern in the carbonyl and alkene stretching region.
3 citations
TL;DR: In this paper , structural features of spiropyrans of the 1,3-benzoxazine-4-one series with various substituents in the 6′ position of the 2H-chromene moiety using single crystal X-ray diffraction analysis, as well as IR and NMR spectroscopy, including various two-dimensional NMR techniques.
3 citations
TL;DR: In this paper , a network of hydrogen bonds was identified as the basis for quantitative yields of macrocycles derived from the dimerization of monomers, and experimental evidence for preorganization derived from macrocycles and acyclic models was derived from NMR spectroscopy and single-crystal X-ray diffraction.
Abstract: In the absence of preorganization, macrocyclization reactions are often plagued by oligomeric and polymeric side products. Here, a network of hydrogen bonds was identified as the basis for quantitative yields of macrocycles derived from the dimerization of monomers. Oligomers and polymers were not observed. Macrocyclization, the result of the formation of two hydrazones, was hypothesized to proceed in two steps. After condensation to yield the monohydrazone, a network of hydrogen bonds formed to preorganize the terminal acetal and hydrazine groups for cyclization. Experimental evidence for preorganization derived from macrocycles and acyclic models. Solution NMR spectroscopy and single-crystal X-ray diffraction revealed that the macrocycles isolated from the cyclization reaction were protonated twice. These protons contributed to an intramolecular network of hydrogen bonds that engaged distant carbonyl groups to realize a long-range order. DFT calculations showed that this network of hydrogen bonds contributed 8.7 kcal/mol to stability. Acyclic models recapitulated this network in solution. Condensation of an acetal and a triazinyl hydrazine, which adopted a number of conformational isomers, yielded a hydrazone that adopted a favored rotamer conformation in solution. The critical hydrogen-bonded proton was also evident. DFT calculations of acyclic models showed that the rotamers were isoenergetic when deprotonated. Upon protonation, however, energies diverged with one low-energy rotamer adopting the conformation observed in the macrocycle. This conformation anchored the network of hydrogen bonds of the intermediate. Computation revealed that the hydrogen-bonded network in the acyclic intermediate contributed up to 14 kcal/mol of stability and preorganized the acetal and hydrazine for cyclization.
2 citations
TL;DR: In this paper , the authors provide experimental chemists and researchers with more computational details and suitable suggestions, and especially hope that this experience may help readers avoid computational pitfalls, which leads, in some cases, to incorrect conclusions by researchers who are not familiar with these methods.
Abstract: With the rapid development of high performance computers and computational methods, including software, an increasing number of experimental chemists have tried to use computational methods such as optical rotation (OR, including the matrix model), optical rotatory dispersion (ORD), electronic circular dichroism (ECD or CD), vibrational circular dichroism (VCD), and magnetic shielding constants—nuclear magnetic resonance (NMR)—to explain and/or assign absolute configuration (AC) for various compounds. Such reports in the field of natural products have increased dramatically. However, every method has its range of application. This leads, in some cases, to incorrect conclusions by researchers who are not familiar with these methods. In this review, we provide experimental chemists and researchers with more computational details and suitable suggestions, and especially hope that this experience may help readers avoid computational pitfalls. Finally, we discuss the use of simplified models to replace original complex structures with a long side chain. The fundamental basis for using models to represent complex chiral compounds, such as in OR calculations, is the existence of conformation pairs with near canceling conformer contributions that justify the use of models rather than the original compounds. Using examples, we here introduce the transition state (TS) calculation, which may benefit readers in this area for use and mastery for their AC study. This review will summarize the general concepts involved in the study of AC determinations.
2 citations
TL;DR: In this paper , the authors reported on the analysis of Arbidol conformational preferences in two solvents of different polarities (deuterated chloroform and dimethyl sulfoxide) using the 2D NOESY method.
Abstract: Understanding of the nucleation process’s fundamental principles in saturated solutions is an urgent task. To do this task, it is necessary to control the formation of polymorphic forms of biologically active compounds. In certain cases, a compound can exist in a single polymorphic form, but have several solvates which can appear in different crystal forms, depending on the medium and conditions of formation, and show different pharmaceutical activity. In the present paper, we report on the analysis of Arbidol conformational preferences in two solvents of different polarities—deuterated chloroform and dimethyl sulfoxide—at 25 °C, using the 2D NOESY method. The Arbidol molecule has various solvate forms depending on the molecular conformation. The method based on the nuclear Overhauser effect spectroscopy was shown to be efficient in the analysis of complex heterocyclic compounds possessing conformation-dependent pseudo-polymorphism. It is one of the types of polymorphism observed in compounds forming crystal solvates. Combined use of NMR methods and X-ray data allowed determining of conformer populations of Arbidol in CDCl3 and DMSO-d6 which were found to be 8/92% and 37/63%, respectively. The preferred conformation in solution is the same that appears in stable crystal solvates of Arbidol.
2 citations
TL;DR: In this article , an indazole metastable-state photoacid with high water solubility up to 70 mM was designed and synthesized, where photoirradiation generates a quinoidal cis-conformer in water instead of the spiro conformer generally expected for a metastable state photoacid.
Abstract: Indazole metastable-state photoacids have been recently applied to modulating local pH of tumor and brain in animal studies. The mechanism of this type of photoacid was previously assumed to be the same as that of the extensively studied merocyanine photoacids. However, this work showed that the photo reaction of indazole photoacid is significantly different from merocyanine photoacid in water. An indazole photoacid with high water solubility up to 70 mM was designed and synthesized. Photoirradiation generates a quinoidal cis-conformer in water instead of the spiro conformer generally expected for a metastable-state photoacid. Although the twisted conformation reduced conjugation between the electron-withdrawing moiety and the acidic moiety, the cis-conformer possesses a higher acidity than that of the trans-conformer due to the unusual quinoidal structure. In organic solvents, the cis-isomer possesses a Kekule structure, which has lower acidity than that of the trans-conformer. In the presence of a weak base, photoirradiation reversibly converted the trans-conformer to the spiroconformer. Experiments showed that deprotonated cis-conformer is the intermediate for both the spiro formation and the reverse cis-to-trans reaction. Addition of an acid stops both reactions and locks the photoproduct to the protonated cis-conformer.
TL;DR: In this paper , two diastereomeric dibenzo[a,c]phenazine 1,2-cyclohexyl bridged diesters were prepared and their phase properties examined.
Abstract: Two diastereomeric dibenzo[a,c]phenazine 1,2-cyclohexyl bridged diesters were prepared and their phase properties examined. While the trans dimer exhibited a broad columnar liquid crystal phase, the cis dimer was amorphous at all temperatures studied. This difference was attributed to the conformational dynamics of the two systems. NMR and DFT studies indicate that both dimers adopt folded and unfolded conformers in solution. While their folded geometries were similar, the trans dimer adopts an extended, largely planar structure, whereas the cis dimer is limited to non-planar unfolded structures and likely disrupts columnar ordering. Geometric constraints imposed by the cylcic linker were also important for columnar stability, with the trans dimer clearing 40 °C lower than the corresponding acyclic 2R,3R-butyl linked dimer, likely because the cyclohexyl group hinders π-π stacking in the unfolded conformation of the former.
TL;DR: In this paper , a simulation framework was developed and used to assign peak features to conformers in an ensemble of rapidly interconverting structures, and the assignment of peaks to discrete dihedral angle populations suggest that structural constraints are attainable under cryogenic conditions.
Abstract: Protein regions which are intrinsically disordered, exist as an ensemble of rapidly interconverting structures. Cooling proteins to cryogenic temperatures for dynamic nuclear polarization (DNP) magic angle spinning (MAS) NMR studies suspends most of the motions, resulting in peaks that are broad but not featureless. To demonstrate that detailed conformational restraints can be retrieved from the peak shapes of frozen proteins alone, we developed and used a simulation framework to assign peak features to conformers in the ensemble. We validated our simulations by comparing them to spectra of α‐synuclein acquired under different experimental conditions. Our assignments of peaks to discrete dihedral angle populations suggest that structural constraints are attainable under cryogenic conditions. The ability to infer ensemble populations from peak shapes has important implications for DNP MAS NMR studies of proteins with regions of disorder in living cells because chemical shifts are the most accessible measured parameter.
TL;DR: In this paper , the structural and spectroscopic analysis of a warfarin derivative (3-(1-(4-fluorophenyl)-3-(2-hydroxyphenyl)3-oxopropyl)-4-hydroxy-2H-chromen-2-one) has been performed with the aim of finding low-lying energy conformations of this compound.
TL;DR: In this article , the conformations of 55 N,N'-diacylhydrazines were systematically investigated using a combination of solution NMR spectroscopy, X-ray crystallography, and density functional theory calculations.
Abstract: N,N'-diacylhydrazines (R1CO-NR3-NR4-COR2) are a class of small molecules with a wide range of applications in chemistry and biology. They are structurally unique in the sense that their two amide groups are connected via a N-N single bond, and as a result, these molecules can exist in eight different isomeric forms. Four of these are amide isomers [trans-trans (t-t), trans-cis (t-c), cis-trans (c-t), and cis-cis (c-c)] arising from C-N bond restricted rotation. In addition, each of these amide isomers can exist in two different isomeric forms due to N-N bond restricted rotation, especially when R3 and R4 groups are relatively bigger. Herein, we have systematically investigated the conformations of 55 N,N'-diacylhydrazines using a combination of solution NMR spectroscopy, X-ray crystallography, and density functional theory calculations. Our data suggest that when the substituents R3 and R4 on the nitrogen atoms are both hydrogens. These molecules prefer twisted trans-trans (t-t) (>90%) geometries (H-N-C═O ∼ 180°), whereas the N-alkylated and N,N'-dialkylated molecules prefer twisted trans-cis (t-c) geometries. Herein, we have analyzed the stabilization of the various isomers of these molecules in light of steric and stereoelectronic effects. We provide a guideline to a priori predict the most stable conformers of the N,N'-diacylhydrazines just by examining their substituents (R1-R4).
TL;DR: In this article , the authors developed a model to rapidly predict solution structures of macrocycles sharing the same Murcko framework, including the efficiency of macrocyclization (quantitative), the solution-and solid-state structures (folded), the site of protonation (opposite the auxiliary dimethylamine group), the geometry of the hydrazone (E), the C2 symmetry of the subunits (conserved), and the rotamer state adopted.
Abstract: Experiment and computation are used to develop a model to rapidly predict solution structures of macrocycles sharing the same Murcko framework. These 24-atom triazine macrocycles result from the quantitative dimerization of identical monomers presenting a hydrazine group and an acetal tethered to an amino acid linker. Monomers comprising glycine and the β-branched amino acids threonine, valine, and isoleucine yield macrocycles G-G, T-T, V-V, and I-I, respectively. Elements common to all members of the framework include the efficiency of macrocyclization (quantitative), the solution- and solid-state structures (folded), the site of protonation (opposite the auxiliary dimethylamine group), the geometry of the hydrazone (E), the C2 symmetry of the subunits (conserved), and the rotamer state adopted. In aggregate, the data reveal metrics predictive of the three-dimensional solution structure that derive from the fingerprint region of the 1D 1H spectrum and a network of rOes from a single resonance. The metrics also afford delineation of more nuanced structural features that allow subpopulations to be identified among the members of the framework. Well-tempered metadynamics provides free energy surfaces and population distributions of these macrocycles. The areas of the free energy surface decrease with increasing steric bulk (G-G > V-V ∼ T-T > I-I). In addition, the surfaces are increasingly isoenergetic with decreasing steric bulk (G-G > V-V ∼ T-T > I-I).
TL;DR: In this article , a conformational analysis of psilocin, a psychedelic molecule was carried out at B3LYP/cc-pVTZ level of theory and a global minimum was identified having highest population among all the local conformers along with second stable conformer which is 5.4 kcal/mol higher in energy than global minimum.
Abstract: Conformational analysis of psilocin, a psychedelic molecule was carried out at B3LYP/cc-pVTZ level of theory. And a global minimum was identified having highest population among all the local conformers along with second stable conformer which is 5.4 kcal/mol higher in energy than global minimum. The global mimimum is stable due to the formation of intramolecular H-bond between ethyl amine nitrogen and indolic hydroxyl group, revealed by AIM (Atoms in molecule) analysis. This is in contradiction to earlier X-ray crystal studies of this molecule reported in literature. Dimers of both stable conformers were studied at same level that is B3LYP/cc-pVTZ and it was observed that the intramolecular H-bond energy dominates over the intermolecular H-bond in the dimers. Other calculations namely NBO (Natural bond orbital), FMO (Frontier molecular orbital), charge analysis, ESP (Electrostatic potential) mapping corroborated the AIM results in a significant manner. The spectroscopic study including UV (Ultraviolet), 1H-NMR (Proton nuclear magnetic resonance) and vibrational modes calculation were found to be in good agreement with the data reported in literature.
04 Jun 2023
TL;DR: In this paper , a multi-scale feature aggregation Conformer (MFA-Conformer) has been proposed for speaker verification, which combines convolution neural network (CNN) and Transformer model for modeling local and global features, respectively.
Abstract: This paper proposes to pretrain Conformer with automatic speech recognition (ASR) task for speaker verification. Conformer combines convolution neural network (CNN) and Transformer model for modeling local and global features, respectively. Recently, multi-scale feature aggregation Conformer (MFA-Conformer) has been proposed for automatic speaker verification. MFA-Conformer concatenates frame-level outputs from all Conformer blocks for further pooling. However, our experiments show that Conformer can be easily overfitted with limited speaker recognition training data. To avoid overfitting, we propose to transfer the knowledge learned from ASR to speaker verification. Specifically, an ASR pretrained Conformer is used to initialize the training of MFA-Conformer for speaker verification. Our experiments show that pretraining Conformer with ASR leads to significant performance gains across model sizes. The best model achieves 0.48%, 0.71% and 1.54% EER on Voxceleb1-O, Voxceleb1-E, and Voxceleb1-H, respectively.
TL;DR: In this article , the authors reported the folding of the flexible side-chain in 3-dimethylamino phenyl propanal (DMAPhP) through a N−C═O n→π* interaction using various computational approaches such as NBO, QTAIM, and NCI analyses.
Abstract: n→π* non-covalent interaction (NCI) and hydrogen bond have similarity in terms of delocalization of the electron density between the two orbitals involved in the interaction. Hydrogen bond (X-H···Y) involves delocalization of the lone pair electrons (n) on the Y atom into the σ* orbital of the X-H bond. In contrast, the n→π* interaction deals with delocalizing the lone pair electrons (n) on the N, O, or S atom into the π* orbital of a C═O group or aromatic ring. Herein, we have shown a resemblance of this weak n→π* interaction with the relatively stronger hydrogen bond in terms of folding the side chains in flexible molecules. This work reports the study of folding of the flexible side-chain in 3-[2-(dimethylamino) phenyl] propanal (DMAPhP) through a N···C═O n→π* interaction using various computational approaches such as NBO, QTAIM, and NCI analyses. The folding of the molecule by the n→π* interaction observed in this study is found to be similar to that present in the secondary structures of peptides or proteins through hydrogen bonding interactions. Interestingly, the stabilization of the global minimum conformer of DMAPhP by the n→π* interaction demonstrates the importance of this NCI in providing conformational preferences in molecular systems. Another important finding of this study is that the theoretical redshift obtained in the C═O stretching frequency of the most stable conformer of the DMAPhP is contributed mostly by the n→π* interaction as the C═O group is not involved in hyperconjugation with any neighboring heteroatom, which is a common phenomenon in any ester or amide. We have also demonstrated here that the strength of the intramolecular n→π* interaction can be modulated by varying the electronic substituents at the para position of the donor group involved in the interaction.
TL;DR: In this article , the emergence of homochirality from achiral precursors is explained by a helical network of multivalent intermolecular interactions during the self-assembly of cage conformers.
Abstract: Without chiral induction the emergence of homochirality from achiral molecules is rather serendipitous, as the rationale is somewhat ambiguous. We herein provide a plausible solution. From achiral precursors are formed a pair of interconverting cage conformers that exhibit a C3-axis as the only symmetry element. When their interconversion is impeded with intramolecular H-bonding, each conformer self-sorts into a homochiral crystal, which is driven by a helical network of multivalent intermolecular interactions during the self-assembly of homochiral cage conformers. As no chiral induction is involved throughout, we believe our study could enlighten the rational design for the emergence of homochirality with several criteria: 1) formation of a molecule without inversion center or mirror plane; 2) suppression of the enantiomeric interconversion, and introduction of multivalent interactions along the helical trajectory of screw symmetry within the resulting superstructure.
TL;DR: In this paper , the authors investigated the dependence of splicing reactions on extein residues by molecular dynamics simulations on eight extein variants, and found that the conformational sampling of the active site residues of the intein enzyme differed among these extein variant.
Abstract: Intein enzymes catalyze the splicing of their flanking polypeptide chains and have found tremendous biotechnological applications. Their terminal residues form the catalytic core and participate in the splicing reaction. Hence, the neighboring N‐ and C‐terminal extein residues influence the catalytic rate. As these extein residues vary depending on the substrate identity, we tested the influence of 20 amino acids at these sites in the Spl DnaX intein and observed significant variation of spliced product as well as N‐ and C‐terminus cleavage product formation. We investigated the dependence of these reactions on the extein residues by molecular dynamics (MD) simulations on eight extein variants, and found that the conformational sampling of the active‐site residues of the intein enzyme differed among these extein variants. We found that the extein variants that sample higher population of near‐attack conformers (NACs) of the active‐site residues undergo higher product formation in our activity assays. Ground state conformers that closely resemble the transition state are referred to as NACs. Very good correlation was observed between the NAC populations from the MD simulations of eight extein variants and the corresponding product formation from our activity assays. Furthermore, this molecular detail enabled us to elucidate the mechanistic roles of several conserved active‐site residues in the splicing reaction. Overall, this study shows that the catalytic power of Spl DnaX intein enzyme, and most likely other inteins, depends on the efficiency of formation of NACs in the ground state, which is further modulated by the extein residues.
TL;DR: Sarma et al. as discussed by the authors constructed a 3D aryl hydrocarbon receptor (AhR) structure from I-TASSER and subjected to molecular dynamics simulations to obtain different structural conformations and determine the most populated AhR conformer by clustering analyses.
Abstract: The aryl hydrocarbon receptor (AhR) has broad biological functions when its ligands activate it; the non-binding interactions with AhR have not been fully elucidated due to the absence of a complete tridimensional (3D) structure. Therefore, utilization of the whole 3D structure from Homo sapiens AhR by in silico studies will allow us to better study and analyze the binding mode of its full and partial agonists, and antagonists, as well as its interaction with the HSP90 chaperone. The 3D AhR structure was obtained from I-TASSER and subjected to molecular dynamics (MD) simulations to obtain different structural conformations and determine the most populated AhR conformer by clustering analyses. The AhR-3D structures selected from MD simulations and those from clustering analyses were used to achieve docking studies with some of its ligands and protein-protein docking with HSP90. Once the AhR-3D structure was built, its Ramachandran maps and energy showed a well-qualified 3D model. MD simulations showed that the per-Arnt-Sim homology (PAS) PAS A, PAS B, and Q domains underwent conformational changes, identifying the conformation when agonists were binding also, and HSP90 was binding near the PAS A, PAS B, and Q domains. However, when antagonists are binding, HSP90 does not bind near the PAS A, PAS B, and Q domains. These studies show that the complex agonist-AhR-HSP90 can be formed, but this complex is not formed when an antagonist is binding. Knowing the conformations when the ligands bind to AHR and the behavior of HSP90 allows for an understanding of its activity.Communicated by Ramaswamy H. Sarma.
TL;DR: In this paper , the microwave spectrum of ethyl butyrate was analyzed in the scope of a systematic investigation to benchmark state-of-the-art exchange correlation functionals and ab initio methods, to accurately predict the lowest energy conformers of carbonyl compounds in their isolated state.
Abstract: High-resolution spectroscopy techniques play a pivotal role to validate and efficiently benchmark available methods from quantum chemistry. In this work, we analyzed the microwave spectrum of ethyl butyrate within the scope of a systematic investigation to benchmark state-of-the-art exchange–correlation functionals and ab initio methods, to accurately predict the lowest energy conformers of carbonyl compounds in their isolated state. Under experimental conditions, we observed two distinct conformers, one of Cs and one of C1 symmetry. As reported earlier in the cases of some ethyl and methyl alkynoates, structural optimizations of the most abundant conformer that exhibits a C1 symmetry proved extremely challenging for several quantum chemical levels. To probe the sensitivity of different methods and basis sets, we use the identified soft-degree of freedom in proximity to the carbonyl group as an order parameter. The results of our study provide useful insight for spectroscopists to select an adapted method for structure prediction of carbonyl compounds based on their available computational resources, suggesting a reasonable trade-off between accuracy and CPU cost. At the same time, our observations and the resulting sets of highly accurate experimental constants from high-resolution spectroscopy experiments give an appeal to theoretical groups to look further into this seemingly simple family of chemical compounds, which may prove useful for the further development and parametrization of theoretical methods in computational chemistry.
TL;DR: In this article , the authors performed a comprehensive crystallographic characterization of two solvates formed by the Y(III) complex with either toluene or dichloromethane.
Abstract: Stabilization of different conformers of sandwich phthalocyaninates by changing the solvation environment has been demonstrated with the examples of new heteroleptic yttrium(III) and terbium(III) triple-decker complexes [(BuO)8Pc]M[(BuO)8Pc]M[(15C5)4Pc] (where M = Y or Tb, [(BuO)8Pc]2- = octa-n-butoxyphthalocyaninato ligand, and [(15C5)4Pc]2- = tetra-15-crown-5-phthalocyaninato ligand). To this end, we have performed a comprehensive crystallographic characterization of two solvates formed by the Y(III) complex with either toluene or dichloromethane. In the solvate with toluene, both pairs of Pc ligands are in staggered conformations, providing both metal cations with a square-antiprismatic environment. In contrast, in the solvate with dichloromethane, only one cation between the BuO- and 15C5-substituted ligands remains in a square-antiprismatic polyhedron, while the pair of BuO-substituted ligands switches to a gauche conformation. In both solvates, the staggered conformations are stabilized by weak interactions of peripheral substituents with solvent molecules. Detailed analysis of the 1H NMR spectra of the isostructural Tb(III) complex in aliphatic and aromatic solvents demonstrates that the stabilization of the corresponding conformations by solvation is also valid in the solution state, resulting in an increase in the axial component of the magnetic susceptibility tensor as the symmetry decreases from staggered to gauche. Thus, solvation-induced conformational switching of lanthanide trisphthalocyaninates can be used as a tool to control their magnetic properties.
TL;DR: In this article , the location of Brønsted-acid sites (bridging OH groups, b-OH) at different crystallographic positions of zeolite catalysts influences their reactivity due to varying confinement.
Abstract: The location of Brønsted-acid sites (bridging OH groups, b-OH) at different crystallographic positions of zeolite catalysts influences their reactivity due to varying confinement. Selecting the most stable b-OH conformers at each of the 12 T-sites (T=Si/Al) of H-MFI, a representative set of 26 conformers is obtained which includes free b-OH groups pointing into the empty pore space and b-OH groups forming H-bonds across five- or six-membered rings of TO4 tetrahedra. Chemically accurate coupled-cluster-quality calculations for periodic models show that the strength of internal H-bonds and, hence, the OH bond length vary substantially with the framework position. For 11 of the 19 H-bonded b-OH groups examined, our predictions fall into the full width at half maximum range of the experimental signals at 3250±175 cm-1 and 7.0±1.4 ppm which supports previously debated assignments of these signals to H-bonded b-OH sites.
TL;DR: In this paper , the authors investigated the influence of DMSO-d6 on the conformational preferences of fenamates, which have similar fragment structures to the molecule, using lidocaine as a model compound.
TL;DR: In this article , a mechanochemical Felkin-Anh model is proposed for predicting the outcome of a nucleophilic addition to an α-chiral ketone, which is entirely based on the distance between the pulling points, maximized in the anti-periplanar arrangement.
Abstract: Anti-Felkin-Anh diastereoselectivity can be achieved for nucleophilic additions to α-chiral ketones upon stretching the ketone with a mechanical pulling force. Herein, a mechanochemical Felkin-Anh model is proposed for predicting the outcome of a nucleophilic addition to an α-chiral ketone. Essentially, the fully stretched chiral ketone has one substituent shielding each side of the carbonyl, in contrast to the Felkin-Anh model, in which free rotation around a bond is required to achieve the two rotamers of the ketone. Depending on the pulling scenario, either Felkin-Anh or anti-Felkin-Anh diastereoselectivity is obtained. The model is entirely based on the distance between the pulling points, which is maximized in the anti-periplanar arrangement. The major diastereomer is associated with the approach with the least steric interactions. The intuitive model is validated by means of mechanochemical density functional theory calculations. Importantly, the ketone is fully stretched in the sub 1 nN force regime, thus minimizing the risk of undesired homolytic bond rupture. Moreover, the mechanical force is not used for lowering the reaction barriers associated with the nucleophilic addition; instead, it is solely applied for locking the conformation of a molecule and provoking otherwise inaccessible reaction pathways on the force-modified potential energy surface.
TL;DR: In this article , the binding affinity of two resorcinol-based acridinedione dyes (ADR1 and ADR2) with the widely studied globular protein Bovine Serum Albumin (BSA) in the presence of site-selective binding drugs by Autodock Vina 4.2 software was employed to ascertain the location of dye in all of the binding sites of BSA.
Abstract: Molecular docking (Mol.Doc) techniques were employed to ascertain the binding affinity of two resorcinol-based acridinedione dyes (ADR1 and ADR2) with the widely studied globular protein Bovine Serum Albumin (BSA) in the presence of site-selective binding drugs by Autodock Vina 4.2 software. Docking of various feasible conformers of ADR1 dye with BSA was found to be energetically more favored than ADR2 dye, even though both these dyes differ in the 9th position of the basic dye structure. Analysis of dyes with BSA establishes the location of dye in all of the binding sites of BSA, predominantly through conventional and nonconventional hydrogen-bonding (HB) interactions. The coexistence of hydrophobic interactions resulted in the stability of various conformers generated. The introduction of site I and site II (Sudlow site binding drugs) into ADR1–BSA and ADR2–BSA complexes effectively destabilizes the dye–protein complex; however, the drugs do not displace ADR dyes completely from their selective binding domains. Site II binding drugs effectively destabilize the binding ability of the dye–protein complex rather than site I drugs. However, docking of site I drug 3-carboxyl-4-methyl-5-propyl-2-furanpropanic acid (CMPF) largely destabilizes the ADR1–protein complex, whereas indomethacin (INDO) enhances the binding affinity of the ADR2–protein complex. Interestingly, simultaneous docking of ADR dyes to the BSA–drug complex results in larger stability of the protein–drug complex through HB interactions rather than hydrophobic interactions. Both ADR1 and ADR2 dyes predominantly occupy the Sudlow binding sites of BSA, and the introduction of either site I or site II binding drugs does not displace the dye efficiently from the corresponding binding sites, rather the drugs are effectively displaced toward other binding domains apart from their specific site-binding domains of BSA. Through Mol.Doc techniques, we authenticate that the interactions in host–guest complex systems involving competing ligands are established in depth, wherein the dye as well as the amino acid (AA) moieties in BSA act as both HB donor and acceptor sites apart from several hydrophobic interactions coexisting toward the stability.
TL;DR: In this article , the authors investigated the distribution patterns of the two GSH conformers from five brain regions, namely, ACC (anterior cingulate cortex), PCC (posterior cingulated cortex), LPC (left parietal cortex), LH (left hippocampus), and CER (cerebellum), using a 3T MRI scanner using MEGA-PRESS pulse sequence in healthy young male and female populations.
Abstract: Glutathione (GSH) is a potent antioxidant synthesized de novo in cells and helps to detoxify free radicals in the brain and other organs. In vitro NMR studies from various research groups have reported primarily two sets of chemical shifts (2.80 or 2.96 ppm) of Cys-βCH2 depending on GSH sample preparation in either inert or oxygenated environments. A multi-center in vivo MRS human study has also validated the presence of two types of GSH conformer in the human brain. Our study is aimed at investigating the distribution patterns of the two GSH conformers from five brain regions, namely, ACC (anterior cingulate cortex), PCC (posterior cingulate cortex), LPC (left parietal cortex), LH (left hippocampus), and CER (cerebellum). GSH was measured using a 3T MRI scanner using MEGA-PRESS pulse sequence in healthy young male and female populations (M/F = 5/9; age 32.8 ± 5.27 years). We conclude that the closed GSH conformer (characteristic NMR shift signature: Cys Hα 4.40-Hβ 2.80 ppm) is more abundant than the extended GSH form (characteristic NMR shift signature Cys Hα 4.56-Hβ 2.95 ppm). Closed conformer has a non-uniform distribution (ACC < CER < LH < PCC < LPC) in the healthy brain. On the contrary, the extended form of GSH has a uniform distribution in various anatomical regions.
TL;DR: In this paper , a general strategy for the accurate computation of conformational and spectroscopic properties of flexible molecules in the gas phase is applied to two representative proteinogenic amino acids with aromatic side chains, namely, phenylalanine and tyrosine.
Abstract: A general strategy for the accurate computation of conformational and spectroscopic properties of flexible molecules in the gas phase is applied to two representative proteinogenic amino acids with aromatic side chains, namely, phenylalanine and tyrosine. The main features of all the most stable conformers predicted by this computational strategy closely match those of the species detected in microwave and infrared experiments. Together with their intrinsic interest, the accuracy of the results obtained with reasonable computer times paves the route for accurate investigations of other flexible bricks of life.