Abundant Conformer Research Articles

Characterizing X-Ray and Solution State Conformations for a Model Qubit System: {Cr7Ni} Ring Rotaxanes on a Mixed Metal Triangle.

The synthesis of a series of [4]rotaxanes, each consisting of three [2]rotaxanes joined via a central {CrNi2} triangular linker, is reported. The resultant four [4]rotaxanes were characterized by single crystal X-ray diffraction and electron paramagnetic resonance (EPR) spectroscopy. Orientation-selective 4-pulse double electron-electron resonance (DEER) measurements between the three {Cr7Ni} rings incorporated in each [4]rotaxane reveal that each system is conformationally fluxional in solution, with the most abundant conformations found to differ significantly from the crystal structure geometry for each compound. The degree of similarity between conformations is evaluated using a novel application of the earth mover's distance analysis.

Conformational Transition of Semiflexible Ring Polyelectrolyte in Tetravalent Salt Solutions: A Simple Numerical Modeling without the Effect of Twisting.

In this work, the conformational behaviors of ring polyelectrolyte in tetravalent salt solutions are discussed in detail through molecular dynamics simulation. For simplification, here we have neglected the effect of the twisting interaction, although it has been well known that both bending and twisting interactions play a deterministic in the steric conformation of a semiflexible ring polymer. The salt concentration CS and the bending energy b take a decisive role in the conformation of the ring polyelectrolyte (PE). Throughout our calculations, the b varies from b = 0 (freely joint chain) to b = 120. The salt concentration CS changes in the range of 3.56 × 10-4 M ≤ CS ≤ 2.49 × 10-1 M. Upon the addition of salt, ring PE contracts at first, subsequently re-expands. More abundant conformations are observed for a semiflexible ring PE. For b = 10, the conformation of semiflexible ring PE shifts from the loop to two-racquet-head spindle, then it condenses into toroid, finally arranges into coil with the increase of CS. As b increases further, four phase transitions are observed. The latter two phase transitions are different. The semiflexible ring PE experiences transformation from toroid to two racquet head spindle, finally to loop in the latter two phase transitions. Its conformation is determined by the competition among the bending energy, cation-bridge, and entropy. Combined, our findings indicate that the conformations of semiflexible ring PE can be controlled by changing the salt concentration and chain stiffness.

Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.

Triple in silico targeting of IMPDH enzyme and RNA-dependent RNA polymerase of both SARS-CoV-2 and Rhizopus oryzae.

Aim: Mucormycosis has been associated with SARS-CoV-2 infections during the last year. The aim of this study was to triple-hit viral and fungal RNA-dependent RNA polymerases (RdRps) and human inosine monophosphate dehydrogenase (IMPDH). Materials & methods: Molecular docking and molecular dynamics simulationwere usedto test nucleotide inhibitors (NIs) against the RdRps of SARS-CoV-2 and Rhizopus oryzae RdRp. These same inhibitors targeted IMPDH. Results: Four NIs revealed a comparable binding affinity to the two drugs, remdesivir and sofosbuvir. Binding energies were calculated using the most abundant conformations of the RdRps after 100-ns molecular dynamics simulation. Conclusion: We suggest the triple-inhibition potential of four NIs against pathogenic RdRps and IMPDH, which is worth experimental validation.

Kinetic Resolution of the Atomic 3D Structures Formed by Ground and Excited Conformational States in an RNA Dynamic Ensemble.

Knowing the 3D structures formed by the various conformations populating the RNA free-energy landscape, their relative abundance, and kinetic interconversion rates is required to obtain a quantitative and predictive understanding of how RNAs fold and function at the atomic level. While methods integrating ensemble-averaged experimental data with computational modeling are helping define the most abundant conformations in RNA ensembles, elucidating their kinetic rates of interconversion and determining the 3D structures of sparsely populated short-lived RNA excited conformational states (ESs) remains challenging. Here, we developed an approach integrating Rosetta-FARFAR RNA structure prediction with NMR residual dipolar couplings and relaxation dispersion that simultaneously determines the 3D structures formed by the ground-state (GS) and ES subensembles, their relative abundance, and kinetic rates of interconversion. The approach is demonstrated on HIV-1 TAR, whose six-nucleotide apical loop was previously shown to form a sparsely populated (∼13%) short-lived (lifetime ∼ 45 μs) ES. In the GS, the apical loop forms a broad distribution of open conformations interconverting on the pico-to-nanosecond time scale. Most residues are unpaired and preorganized to bind the Tat-superelongation protein complex. The apical loop zips up in the ES, forming a narrow distribution of closed conformations, which sequester critical residues required for protein recognition. Our work introduces an approach for determining the 3D ensemble models formed by sparsely populated RNA conformational states, provides a rare atomic view of an RNA ES, and kinetically resolves the atomic 3D structures of RNA conformational substates, interchanging on time scales spanning 6 orders of magnitude, from picoseconds to microseconds.

Insights into thiram fungicide: A comparative study of solution and solid phases through Raman, DCDR, and SERS measurements and DFT simulations

AbstractThiram, a widely known fungicide, has evinced a negative impact on the environment and human health that led to the banning of its use in plant protection products on all commodities in the European Union. Therefore, there is a need for monitoring possible illicit use, which requires sensitive and accurate detection methods. In this study, the behavior of thiram in different phases was investigated in order to better understand its properties. Raman spectra were obtained from thiram in the solid state as a crystalline powder, dissolved in different solvents, and from dried deposits using the drop coating deposition Raman (DCDR) method. The analyses of acquired Raman spectra revealed evidence of hydrogen bonding between thiram and chloroform in the solution phase. The reliability and sensitivity of DCDR measurements were also highlighted, with high‐quality spectra obtained from a dried pattern from droplet at a 40 μM concentration. Moreover, the study identified the most abundant conformer of intact (undegraded) thiram molecule and enabled reliable band assignment and vibrational analysis based on DFT simulations, providing a better understanding of the compound's properties. The results also suggested that thiram can be coordinated to silver in nanostructured SERS active substrates not only in the degraded form but also in the undegraded form. Overall, this study provides valuable insights into thiram's behavior and can be helpful in the further development of efficient and effective methods for its detection and analysis.

Hexahexyloxycalix[6]arene, a Conformationally Adaptive Host for the Complexation of Linear and Branched Alkylammonium Guests.

Hexahexyloxycalix[6]arene 2b leads to the endo-cavity complexation of linear and branched alkylammonium guests showing a conformational adaptive behavior in CDCl3 solution. Linear n-pentylammonium guest 6a+ induces the cone conformation of 2b at the expense of the 1,2,3-alternate, which is the most abundant conformer of 2b in the absence of a guest. In a different way, branched alkylammonium guests, such as tert-butylammonium 6b+ and isopropylammonium 6c+, select the 1,2,3-alternate as the favored 2b conformation (6b+/6c+⊂2b1,2,3-alt), but other complexes in which 2b adopts different conformations, namely, 6b+/6c+⊂2bcone, 6b+/6c+⊂2bpaco, and 6b+/6c+⊂2b1,2-alt, have also been revealed. Binding constant values determined via NMR experiments indicated that the 1,2,3-alternate was the best-fitting 2b conformation for the complexation of branched alkylammonium guests, followed by cone > paco > 1,2-alt. Our NCI and NBO calculations suggest that the H-bonding interactions (+N-H···O) between the ammonium group of the guest and the oxygen atoms of calixarene 2b are the main determinants of the stability order of the four complexes. These interactions are weakened by increasing the guest steric encumbrance, thus leading to a lower binding affinity. Two stabilizing H-bonds are possible with the 1,2,3-alt- and cone-2b conformations, whereas only one H-bond is possible with the other paco- and 1,2-alt-2b stereoisomers.

The effect of histidine behaviors on the structural properties of Aβ(1-42) peptide in protonation stage one, two, and three.

Histidine behaviors (including tautomeric and protonation behaviors, and integration on ε, δ, or p states) have been linked to protein folding and misfolding. However, the histidine behaviors of Aβ(1-42) are unconfirmed, which is the key point to understanding the pathogenesis of Alzheimer's disease. In the current study, 19 replica exchange molecular dynamics (REMD) simulations were performed to investigate the impact of histidine on the structural properties in protonation evolution stages one, two, and three. In contrast to the deprotonated (εεε) state, our current findings demonstrate that any protonated state will promote the formation of the β-sheet structure. The sheet-rich structures of (pεε), (δεp), (pεp), and (ppp) have the same basic characteristics of three-strand structures between the N-terminus, central hydrophobic core (CHC), and C-terminus. We found that the (pεε) (probability of 77.7%) and (δεp) (probability of 60.2%) prefer the abundant conformation over the other systems with higher regularity antiparallel β-sheet structure characteristics. Further H-bonding results indicate that H6 and H14 are more essential than H13. In addition, the Pearson correlation coefficient analysis revealed that the experimental result coincided with our simulated (δpε) system. The current study aids in the better understanding of the mechanisms of histidine behaviors, providing a fresh outlook on protein folding and misfolding.

Conformational Panorama of Cycloundecanone: A Rotational Spectroscopy Study.

The conformational landscape of the medium-size cyclic ketone cycloundecanone has been investigated using chirped-pulse Fourier transform microwave spectroscopy and computational calculations. Nine conformations were observed in the rotational spectrum and identified from the comparison of experimental and theoretical rotational constants as well as the observed and predicted types of rotational transitions. All singly substituted 13C isotopologues were observed for the most abundant conformer, which allowed the determination of partial substitution and effective structures. The most abundant conformer dominates the rotational spectrum and is almost 40 times more abundant than the least abundant conformer. Conformational preferences are governed by the combination of transannular H···H and eclipsed HCCH interactions.

Molecular dynamics of fibric acids.

1H- and 13C-NMR chemical shifts were measured for four fibric acids (bezafibrate, clofibric acid, fenofibric acid, and gemfibrozil), which are lipid-lowering drugs. Correlation is found with DFT-computed chemical shifts from the conformational analysis. Equilibrium populations of optimized conformers at 298 K are very different when based on computed Gibbs energies rather than on potential energies. This is due to the significant entropic advantages of extended rather than bent conformational shapes. Abundant conformers with intramolecular hydrogen bonding via five-member rings are computed for three fibric acids, but not gemfibrozil, which lacks suitable connectivity of carboxyl and phenoxy groups. Trends in computed atom-positional deviations, molecular volumes, surface areas, and dipole moments among the fibric acids and their constituent conformations indicate that bezafibrate has the greatest hydrophilicity and fenofibric acid has the greatest flexibility. Theoretical and experimental comparison of chemical shifts of standards with sufficient overlap of fragments containing common atoms, groups, and connectivity may provide a reliable minimal set to benchmark and generate leads.

Quantitative Study of Enantiomer-Specific State Transfer.

We here report on a quantitative study of enantiomer-specific state transfer, performed in a pulsed, supersonic molecular beam. The chiral molecule 1-indanol is cooled to low rotational temperatures (1-2K) and a selected rotational level in the electronic and vibrational ground state of the most abundant conformer is depleted via optical pumping on the S_{1}←S_{0} transition. Further downstream, three consecutive microwave pulses with mutually perpendicular polarizations and with a well-defined duration and phase are applied. The population in the originally depleted rotational level is subsequently monitored via laser-induced fluorescence detection. This scheme enables a quantitative comparison of experiment and theory for the transfer efficiency in what is the simplest enantiomer-specific state transfer triangle for any chiral molecule, that is, the one involving the absolute ground state level, |J_{K_{a}K_{c}}⟩=|0_{00}⟩. Moreover, this scheme improves the enantiomer enrichment by over an order of magnitude compared to previous works. Starting with a racemic mixture, a straightforward extension of this scheme allows one to create a molecular beam with an enantiomer-pure rotational level, holding great prospects for future spectroscopic and scattering studies.

Revealing the Structure and Noncovalent Interactions of Isolated Molecules by Laser-Desorption/Ionization-Loss Stimulated Raman Spectroscopy and Quantum Calculations.

The structural and dynamical characteristics of isolated molecules are essential, yet obtaining this information is difficult. We demonstrate laser-desorption jet-cooling/ionization-loss stimulated Raman spectroscopy to obtain Raman spectral signatures of nonvolatile molecules in the gas phase. The vibrational features of a test substance, the most abundant conformer of tryptamine, are compared and found to match those resulting from the scaled harmonic Raman spectrum obtained by density functional theory calculations. The vibrational signatures serve to identify the most prominent gauche conformer and evaluate its predicted electronic structure. These findings, together with noncovalent interaction (NCI) analysis, provide new insights into electron densities and reduced density gradients, assessing the hydrogen bonds (N-H···π and C-H···H-C) and interplay between attractive and repulsive NCIs affecting the structure. This approach accesses vibrational signatures of isolated nonvolatile molecules by tabletop lasers at uniform resolution and in a broad frequency range, promising great benefit to future studies.

Chiral Conformation of Subnanometric Materials.

Subnanometric materials (SNMs) refer to nanomaterials with sizes comparable to the diameter of common linear polymers or confined at the level of a single unit cell in at least one dimension, usually <1 nm. Conventional inorganic nanoparticles are usually deemed to be rigid, lacking self-adjustable conformation. In contrast, the size at subnanometric scale endows SNMs with flexibility analogous to polymers, resulting in their abundant self-adjustable conformation. It is noteworthy that some highly flexible SNMs can adjust their shape automatically to form chiral conformation, which is rare in conventional inorganic nanoparticles. Herein, we summarize the chiral conformation of SNMs and clarify the driving force behind their formation, in an attempt to establish a better understanding for the origin of flexibility and chirality at subnanometric scale. In addition, the general strategies for controlling the conformation of SNMs are elaborated, which might shed light on the efficient fabrications of chiral inorganic materials. Finally, the challenges facing this area as well as some unexplored topics are discussed.

Revisiting conformations of methyl lactate in water and methanol.

The recently developed efficient protocols to implicit [Grimme et al., J. Phys. Chem. A 125, 4039-4054 (2021)] and explicit quantum mechanical modeling of non-rigid molecules in solution [Katsyuba et al., J. Phys. Chem. B 124, 6664-6670 (2020)] are applied to methyl lactate (ML). Building upon this work, a new combination scheme is proposed to incorporate solvation effects for the computation of infrared (IR) absorption spectra. Herein, Boltzmann populations calculated for implicitly solvated single conformers are used to weight the IR spectra of explicitly solvated clusters with a size of typically ten solvent molecules, i.e., accounting for the first solvation shell. It is found that in water and methanol, the most abundant conformers of ML are structurally modified relative to the gas phase, where the major form is ML1, in which the syn conformation of the -OH moiety is stabilized by a OH⋯O=C intramolecular hydrogen bond (HB). In solution, this syn conformation transforms to the gauche form because the intramolecular HB is disrupted by explicit water molecules that form intermolecular HBs with the hydroxyl and carbonyl groups. Similar changes induced by the gas-solution transition are observed for the minor conformers, ML2 and/or ML3, characterized by OH⋯OCH3 intramolecular HB in the gas phase. The relative abundance of ML1 is shown to decrease from ∼96% in gas to ∼51% in water and ∼92% in methanol. The solvent strongly influences frequencies, IR intensities, and normal modes, resulting in qualitatively different spectra compared to the gas phase. Some liquid-state conformational markers in the fingerprint region of IR spectra are revealed.

Identifying Conformational Isomers of Organic Molecules in Solution via Unsupervised Clustering.

We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterized by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the Fast Search and Find of Density Peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase, and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that while Sildenafil can adopt more than 100 metastable conformational configurations, only 12 are significantly populated across all of the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.

Characterizing protein conformers by cross-linking mass spectrometry and pattern recognition.

Chemical cross-linking coupled to mass spectrometry (XLMS) emerged as a powerful technique for studying protein structures and large-scale protein-protein interactions. Nonetheless, XLMS lacks software tailored toward dealing with multiple conformers; this scenario can lead to high-quality identifications that are mutually exclusive. This limitation hampers the applicability of XLMS in structural experiments of dynamic protein systems, where less abundant conformers of the target protein are expected in the sample. We present QUIN-XL, a software that uses unsupervised clustering to group cross-link identifications by their quantitative profile across multiple samples. QUIN-XL highlights regions of the protein or system presenting changes in its conformation when comparing different biological conditions. We demonstrate our software's usefulness by revisiting the HSP90 protein, comparing three of its different conformers. QUIN-XL's clusters correlate directly to known protein 3D structures of the conformers and therefore validates our software. QUIN-XL and a user tutorial are freely available at http://patternlabforproteomics.org/quinxl for academic users. Supplementary data are available at Bioinformatics online.

Analysis of Cooperativity and Group Additivity in the Hydration of 1,2-Dimethoxyethane.

We calculate hydration free energies of 1,2-dimethoxyethane (DME) conformations in water at 298 K and 1 bar. We find that the preference for the two most abundant tgt and tgg conformations derives from favorable nonspecific (i.e., long-range) solute-water interactions that are partially offset by unfavorable free energies of forming cavities in water to accommodate these conformations. The much lower population of the third most abundant tg+g- conformation, the most abundant conformation in the ideal gas at 298 K, is attributed to less favorable long-range solute-water interactions. We also find that long-range methyl/methylene group-water and ether oxygen-water interactions make significant nonadditive contributions to the free energy of DME hydration and propose a method based on quasichemical theory for reducing these nonadditive contributions by identifying constituent groups of DME that minimize the covariance in the long-range methyl/methylene group-water and ether oxygen-water interactions. We apply this method to show that the decomposition of DME into its constituent dimethyl ether groups is a better approximation of group additivity than decompositions based on distinguishing hydrophobic/hydrophilic constituent groups.

Molecular structure of 1,2-diethyldiaziridine studied by gas electron diffraction supported by quantum chemistry calculations

The molecular structure of 1,2-diethyldiaziridine was studied by gas-phase electron diffraction (GED) and quantum chemical calculations. Best fitting to GED experiment scattering intensities was obtained for three conformer model. The experimental structural parameters of most abundant conformer of 1,2-diethyldiaziridine are following (rh1 bond lengths in Å, bond angles in degrees with 3σ in parentheses): r(NCcycl), 1.446(4); r(NN), 1.492(5); r(CC), 1.528(3); r(NCacycl), 1.459(6); ∠NCC, 112.3(11); ∠CNC, 114.7(6). The gas phase standard enthalpy of formation of 1,2-diethyldiaziridine was calculated using Gaussian-4 theory, giving the value of 148.3 ± 3.3 kJ/mol. 1H and 13C NMR spectra obtained in CDCl3 solution were compared with DFT predictions.

Structure of Proton-Bound Methionine and Tryptophan Dimers in the Gas Phase Investigated with IRMPD Spectroscopy and Quantum Chemical Calculations.

The structures of three proton-bound dimers (Met2H+, MetTrpH+, and Trp2H+) are investigated in the gas phase with infrared multiple photon disassociation (IRMPD) spectroscopy in combination with quantum chemical calculations. Their IRMPD spectra in the range of 600–1850 cm–1 are obtained experimentally using an FT-ICR mass spectrometer and the CLIO free electron laser as an IR light source. The most abundant conformers are elucidated by comparing the IRMPD spectra with harmonic frequencies obtained at the B3LYP-GD3BJ/6-311++G** level of theory. Discrepancies between the experimental and theoretical data in the region of 1500–1700 cm–1 are attributed to the anharmonicity of the amino bending modes. We confirm the result of a previous IRMPD study that the structure of gas-phase Trp2H+ is charge-solvated but find that there are more stable structures than originally reported (Feng, R.; Yin, H.; Kong, X. Rapid Commun. Mass Spectrom.2016, 30, 24–28). In addition, gas-phase Met2H+ and MetTrpH+ have been revealed to have charge-solvated structures. For all three dimers, the most stable conformer is found to be of type A. The spectrum of Met2H+, however, cannot be explained without some abundance of type B charge-solvated conformers as well as salt-bridged structures.

Theoretical Spectroscopic Studies on Chemical and Electronic Structures of Selenocysteine and Pyrrolysine

The chemical and electronic structures of the 21st and 22nd proteinogenic amino acid selenocysteine (Sec), pyrrolysine (Pyl) and their derivatives (deprotonated and protonated ions) were extensively characterized for the first time. Through the fragment based step-by-step research on their potential energy surface (PES), electronic energies of the most stable conformers of Sec, Pyl and the related ions were finally determined at the advanced CBS-QB3 and DSD-PBEP86-D3(BJ)/aug-cc-pVTZ level, respectively, with the identification of many new low-energy conformers. The infrared spectra (IR) at 298 K of the most abundant conformers in different forms were scaled by comparison with the anharmonic frequency calculations and analyzed comparing with the experimental spectra of similar molecules. The characteristic soft X-ray spectra (including X-ray photoelectron spectra (XPS) and near-edge X-ray absorption fine-structure spectra (NEXAFS)) of the most stable conformers at 498 K were also simulated. Especially, the two possible protonated configurations of Pyl can be clearly distinguished by their different spectral features. Furthermore, a small binding energy intersection appeared around 293 eV at the C 1s edge between the canonical and protonated Pyl conformers, which is different from all the previous study on similar molecules. This work thus filled the gap in our knowledge by providing detailed information on the chemical and electronic structures of Sec and Pyl and will be a useful guidance for future experimental research.