Showing papers on "Conformational isomerism published in 2010"
TL;DR: In this article, a conformational analysis of 7-acetoxy-6-(2,3-dibromopropyl)-4,8-dimethylcoumarin molecule (abbreviated as 7ADDC) was performed by using ab initio Hartree-Fock (HF) method with 3-21G as the basis set to find the most stable form of 7ADdc.
206 citations
TL;DR: Temperature-accelerated molecular dynamics generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens.
Abstract: We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168-175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t --> r('') transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 A, with a twist of 90 degrees relative to the equatorial domain, and the root-mean-squared deviation relative to the r('') conformer is reduced from 13 to 5 A, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 A from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal/mol for the free-energy barrier between conformers in both cases.
162 citations
TL;DR: The results show that the signal in high‐resolution electron density maps extends below the traditional 1 σ cutoff, and crystalline proteins are more polymorphic than current crystallographic models.
Abstract: Although proteins populate large structural ensembles, X-ray diffraction data are traditionally interpreted using a single model. To search for evidence of alternate conformers, we developed a program, Ringer, which systematically samples electron density around the dihedral angles of protein side chains. In a diverse set of 402 structures, Ringer identified weak, nonrandom electron-density features that suggest of the presence of hidden, lowly populated conformations for >18% of uniquely modeled residues. Although these peaks occur at electron-density levels traditionally regarded as noise, statistically significant (P < 10 25 ) enrichment of peaks at successive rotameric v angles validates the assignment of these features as unmodeled conformations. Weak electron density corresponding to alternate rotamers also was detected in an accurate electron density map free of model bias. Ringer analysis of the high-resolution structures of free and peptide-bound calmodulin identified shifts in ensembles and connected the alternate conformations to ligand recognition. These results show that the signal in high-resolution electron density maps extends below the traditional 1 r cutoff, and crystalline proteins are more polymorphic than current crystallographic models. Ringer provides an objective, systematic method to identify previously undiscovered alternate conformations that can mediate protein folding and function.
157 citations
TL;DR: The programmed geometry and functionality of the molecular module together with its conformational flexibility and substrate interaction yields sinuous metal-organic polymeric assemblies, based on an unusual two-fold Cu-pyridyl coordination motif, which indicates that the lateral bonding motif is predominantly independent of the substrate.
Abstract: We employed a de novo synthesized porphyrin module to construct one-dimensional (1D) Cu-coordinated polymers on Cu(111) and Ag(111) surfaces. The programmed geometry and functionality of the molecular module together with its conformational flexibility and substrate interaction yields sinuous metal−organic polymeric assemblies, based on an unusual two-fold Cu−pyridyl coordination motif. An analysis of scanning tunneling microscopy (STM) data reveals the occurrence of two enantiomers, resulting from the surface confinement that deconvolutes the module in 2D-chiral conformational isomers. The stereoisomers exhibit site-specific surface anchoring, from whence three discrete orientations are possible for each species. Their sequence and mutual arrangement determine direction and curvature of the metal−organic chains. The Cu-coordinated polymers are very similar on both Cu(111) and Ag(111), where their formation is induced by intrinsic and coevaporated adatoms, respectively, which indicates that the lateral bo...
148 citations
TL;DR: In this paper, two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P1 space group, and novel forms 2 and 3 in P21/n and P 1 space groups.
Abstract: Two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P1 space group, and novel forms 2 and 3 in P21/n and P1 space groups. The conformationally flexible molecule 4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid has variable torsions at the sulfonamide and furyl ring portions in conformers which lie in a 6 kcal mol−1 energy window. A conformer surface map was calculated to show that the two conformations in crystal form 1 are ∼4.5 kcal mol−1 less stable than conformers present in forms 2 and 3 (0.7, 0.0 kcal mol−1). The stabilization of molecular conformations is analyzed in terms of attractive intramolecular N−H···Cl hydrogen bonds and minimization of repulsive S═O···Cl interactions. Phase stability relationships confirm the thermodynamic nature of form 1 in grinding and slurry experiments by X-ray powder diffraction and infrared spectroscopy. Despite the...
126 citations
TL;DR: Improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states.
Abstract: A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states.
125 citations
TL;DR: This new hypothesis suggests that the stereoselectivity is dictated by two interrelated conformational properties of the reactive complex, namely, the conformational preferences of the oxacarbenium pyranose ring, modulating the steric crowding and exposure of the anomeric carbon toward the α or β face.
Abstract: The mechanism of solvent effects on the stereoselectivity of glycosylation reactions is investigated using quantum-mechanical (QM) calculations and molecular dynamics (MD) simulations, considering a methyl-protected glucopyranoside triflate as a glycosyl donor equivalent and the solvents acetonitrile, ether, dioxane, or toluene, as well as gas-phase conditions (vacuum). The QM calculations on oxacarbenium-solvent complexes do not provide support to the usual solvent-coordination hypothesis, suggesting that an experimentally observed β-selectivity (α-selectivity) is caused by the preferential coordination of a solvent molecule to the reactive cation on the α-side (β-side) of the anomeric carbon. Instead, explicit-solvent MD simulations of the oxacarbenium-counterion (triflate ion) complex (along with corresponding QM calculations) are compatible with an alternative mechanism, termed here the conformer and counterion distribution hypothesis. This new hypothesis suggests that the stereoselectivity is dictated by two interrelated conformational properties of the reactive complex, namely, (1) the conformational preferences of the oxacarbenium pyranose ring, modulating the steric crowding and exposure of the anomeric carbon toward the α or β face, and (2) the preferential coordination of the counterion to the oxacarbenium cation on one side of the anomeric carbon, hindering a nucleophilic attack from this side. For example, in acetonitrile, the calculations suggest a dominant B2,5 ring conformation of the cation with preferential coordination of the counterion on the α side, both factors leading to the experimentally observed β selectivity. Conversely, in dioxane, they suggest a dominant (4)H3 ring conformation with preferential counterion coordination on the β side, both factors leading to the experimentally observed α selectivity.
119 citations
TL;DR: Thermodynamic quantities for conformational isomerism of TFSA(-) from trans to cis isomers in the neat ionic liquid and also in the first solvation sphere of the lithium ion were successfully evaluated for the first time.
Abstract: Raman spectra of the ionic liquid, 1-butyl-3-methylimidazolium bis-(trifluoromethanesulfonyl)amide [C4mIm][TFSA] containing a LiTFSA salt were measured for the lithium salt mole fractions xLi = 0.000, 0.053, 0.106, and 0.171 in the temperature range of 273−350 K. The lithium ion solvation number of 2 at ambient temperature is kept constant in higher temperatures examined in this study. Thermodynamic quantities, such as Gibbs free energy, ΔisoG0; enthalpy, ΔisoH0; and entropy, ΔisoS0, for conformational isomerism of TFSA− from trans to cis isomers in the neat ionic liquid and also in the first solvation sphere of the lithium ion were successfully evaluated for the first time. In the neat ionic liquid, the thermodynamics quantities indicates that the trans isomer is slightly stabilized by enthalpy, though the enthalpic advantage is reduced by entropy to yield nearly equal Gibbs free energy. For the TFSA− in the first solvation sphere of the lithium ion, the ΔisoG0, ΔisoH0, and TΔisoS0 were obtained at 298 K...
106 citations
TL;DR: The methods demonstrated here offer an approach to characterizing conformational variation within the folded or unfolded states of proteins and peptides.
Abstract: Isotope-edited two-dimensional infrared spectroscopy has been used to characterize the conformational heterogeneity of the β-hairpin peptide TrpZip2 (TZ2) across its thermal unfolding transition. Four isotopologues were synthesized to probe hydrogen bonding and solvent exposure of the β-turn (K8), the N-terminus (S1), and the midstrand region (T10 and T3T10). Isotope-shifts, 2D lineshapes, and other spectral changes to the amide I 2D IR spectra of labeled TZ2 isotopologues were observed as a function of temperature. Data were interpreted on the basis of structure-based spectroscopic modeling of conformers obtained from extensive molecular dynamics simulations. The K8 spectra reveal two unique turn geometries, the type I′ β-turn observed in the NMR structure, and a less populated disordered or bulged loop. The data indicate that structures at low temperature resemble the folded NMR structure with typical cross-strand hydrogen bonds, although with a subpopulation of misformed turns. As the temperature is ra...
101 citations
TL;DR: In this paper, a series of β-substituted α-fluoroethanes (F-CH 2 CH 2 -X) have been explored where the substituent X was varied as NH 3 +, OCOH, NCO, NO 2, NHCHO, F, N 3, CH NH, NCS, CH C CH 2, CH 3, CH CH 2, NC, CN, and CCH.
101 citations
TL;DR: C4-endo ring-puckered proline derivatives are presented in which the trans conformer is favored because of a hydrogen-bond-donating substituent in the g position and the versatility of these derivatives to stabilize trans amide bonds within longer peptides is demonstrated.
Abstract: Isomerizations between cis and trans conformers in Xaa–Pro amide bonds (Xaa = any amino acid, Pro = proline) are crucial in many natural processes such as protein folding and signal transduction. Both the understanding of the factors that determine the cis/trans conformer ratio and the development of tools that allow for the tuning of this equilibrium is therefore important. Proline derivatives with a substituent in the g position (C4) have proven useful in both respects (Scheme 1a). Conformational studies have shown that the nature of the substituent at C4 and the absolute configuration at this center critically influence both the pyrrolidine ring pucker and the cis/trans conformer ratio of the amide bond in Xaa–Pro bonds. In all of these proline derivatives, a correlation between the ring pucker and the cis/trans conformer ratio has been observed: A C4-exo ring pucker favors the trans conformation, whereas a C4-endo ring pucker leads to a higher population of the cis conformer. This observation has been attributed to a stronger noncovalent interaction between adjacent amide bonds through an n!p* interaction in the C4-exo compared to C4-endopuckered proline derivatives (Scheme 1 b). As a result, a variety of proline derivatives are available as tools to stabilize the trans conformer of Xaa–Pro bonds in which the proline ring adopts a C4-exo ring pucker. However, within many peptides and proteins the preferred ring pucker of proline with trans amide bonds is not C4-exo but C4-endo. Thus, proline derivatives that preferentially adopt a C4-endo conformation and favor the trans conformer are important alternative probes and have not been developed to date. Herein we present C4-endo ring-puckered proline derivatives in which the trans conformer is favored because of a hydrogen-bond-donating substituent in the g position. Furthermore, we demonstrate the versatility of these derivatives to stabilize trans amide bonds within longer peptides. We started our investigations by an analysis of the relative orientation of the carbonyl groups in acetylated methyl esters of proline derivatives with substituents at C4, which have proven as valuable model compounds for Xaa–Pro bonds. This orientation is crucial because the n!p* interaction that stabilizes the trans conformer requires a B rgi–Dunitz trajectory between the oxygen atom of the acetyl group (Oi 1) and the carbonyl group of the methyl ester (Ci=Oi) as well as a short distance between Oi 1 and Ci (Scheme 1b, right). [7,10]
TL;DR: It is concluded that all of the phase transitions of [C(4)mim]PF(6) except the glass transition are associated with conformational changes of the butyl group.
Abstract: We have investigated phase-transition behaviors of a typical room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([C4mim]PF6), using calorimetric and Raman spectroscopic techniques. Although there was some confusion on its phase behaviors in previous reports, our measurements with a laboratory-made calorimeter at a slow scanning rate (5 mK/s) have definitely revealed that [C4mim]PF6 has three crystalline phases. From the Raman spectroscopic study, the conformations of the butyl group for these crystalline phases are assigned to gauche−trans, trans−trans, and gauche’−trans conformations in lower-energy order. It has been also shown that these three conformers coexist in the liquid, supercooled liquid, and glass states. It is concluded that all of the phase transitions of [C4mim]PF6 except the glass transition are associated with conformational changes of the butyl group.
TL;DR: In this article, a series of straight-chain perfluoroalkyl carboxylic acids (PFCAs) were investigated using semi-empirical, ab initio, density functional theory (DFT) and various solvation models on a homologous series of PFCAs.
Abstract: Computational studies were conducted using the major levels of semiempirical, ab initio, density functional theory (DFT), and the CBS-Q//B3 method and various solvation models on a homologous series of straight chain perfluoroalkyl carboxylic acids (PFCAs) ranging in chain length from C 1 (trifluoroacetic acid) to C 9 ( n -perfluorodecanoic acid) as well as the monomethyl branched C 7 ( n -perfluorooctanoic acid; n -PFOA) isomers. Regardless of perfluoroalkyl chain length and theoretical method employed, application of a computational thermodynamic cycle indicated no significant change in the estimated aqueous monomeric p K a values between C 1 and C 9 , all having a relatively constant p K a of about 0 that is in agreement with earlier predictions and recent experimental evidence. Perfluoroalkyl chain helicity does not appear to result in increased monomeric PFCA p K a values at chain lengths greater than 5. Increasing chain length does not substantially influence the structural or electronic character of the carboxylic acid head group. A MMFF94 conformational search yielded 2915 separate low- through high-energy conformers of n -PFOA. Ranking of these structures gave the 94 lowest MMFF94 energy conformations that were subjected to DFT investigations. Application of a thermodynamic cycle approach, coupled with aqueous and gas phase DFT calculations on the molecular and anionic forms for each of the conformers, gave conformationally averaged p K a values for n -PFOA equal to the global minimum helical conformer p K a . The conformational populations under study occupy ∼100% of the global n -PFOA conformational space, indicating no higher energy/low acidity conformations remain unexamined that could influence the predicted composite aqueous monomeric p K a of zero for this compound.
TL;DR: It is shown that Ala possesses no symmetry, has several large-amplitude nuclear motions, and exhibits conformers with different hydrogen bonding patterns, it is one of the most difficult cases where reliable equilibrium structures have now been determined.
Abstract: The two lowest-energy gas-phase conformers, Ala-I and Ala-IIA, of the natural amino acid L-alanine (Ala) have been investigated by means of rigorous ab initio computations. Born-Oppenheimer (BO) equilibrium structures (re ) were fully optimized at the coupled-cluster (CCSD(T)/cc-pVTZ) level of electronic structure theory. Corresponding semiexperimental (SE) equilibrium structures (re ) of each conformer were determined for the first time by least-squares refinement of 11-15 structural parameters on modified, experimental rotational constant data from 10 isotopologues. The SE equilibrium rotational constants were obtained by, first, refitting Fourier transform microwave spectra using the method of predicate observations and, second, correcting the resulting effective rotational constants with theoretical vibration-rotation interaction constants (Ri). Careful analysis is made of the procedures to account for vibrational distortion, which proves essential to defining precise structures in flexible molecules such as Ala. Because Ala possesses no symmetry, has several large-amplitude nuclear motions, and exhibits conformers with different hydrogen bonding patterns, it is one of the most difficult cases where reliable equilibrium structures have now been determined. The relative energy of the alanine conformers was pinpointed using first-principles composite focal point analyses (FPA), which employed extrapolations using basis sets as large as aug-cc-pV5Z and electron correlation treatments as extensive as CCSD(T). The FPA computations place the Ala-IIA equilibrium structure higher in energy than that of Ala-I by a mere 0.45 kJ mol -1 (38 cm -1 ), showing that the two lowest-lying conformers of alanine are nearly isoenergetic; inclusion of zero-point vibrational energy increases the relative energy to 2.11 kJ mol -1 (176 cm -1 ). The yet unobserved Ala-IIB conformer is found to be separated from Ala-IIA by a vibrationally adiabatic isomerization barrier of only 16 cm -1 .
TL;DR: This model is in agreement with the observed differences in the IR spectra in nitrogen and argon matrices, in particular, the relative frequencies of the νOH and τCOH modes and the relative intensities of theλOH and νC=O bands.
Abstract: Formic acid (HCOOH, FA) and acetic acid (CH3COOH, AA) are studied in a nitrogen matrix. The infrared (IR) spectra of cis and trans conformers of these carboxylic acids (and also of the HCOOD isotopologue of FA) are reported and analyzed. The higher-energy cis conformer of these molecules is produced by narrowband near-IR excitation of the more stable trans conformer, and the cis-to-trans tunneling decay is evaluated spectroscopically. The tunneling process in both molecules is found to be substantially slower in a nitrogen matrix than in rare-gas matrices, the cis-form decay constants being approximately 55 and 600 times smaller in a nitrogen matrix than in an argon matrix, for FA and AA respectively. The stabilization of the higher-energy cis conformer is discussed in terms of specific interactions with nitrogen molecule binding with the OH group of the carboxylic acid. This model is in agreement with the observed differences in the IR spectra in nitrogen and argon matrices, in particular, the relative f...
TL;DR: In this article, the structures and vibrations of 5-fluoro-salicylic acid and 5-chloro-salinic acid (5-FSA, 5-ClSA, C7H5FO3 and C 7H5ClO3) were analyzed using a scaled quantum mechanics (SQM) method.
Abstract: The experimental and theoretical study on the structures and vibrations of 5-fluoro-salicylic acid and 5-chloro-salicylic acid (5-FSA and 5-ClSA, C7H5FO3 and C7H5ClO3) is presented. The Fourier transform infrared spectra (4000–400 cm−1) and the Fourier transform Raman spectra (4000–50 cm−1) of the title molecules in the solid phase were recorded. The molecular structures, vibrational wavenumbers, infrared intensities, Raman intensities and Raman scattering activities were calculated for a pair of molecules linked by the intermolecular OH···O hydrogen bond. The geometrical parameters and energies of 5-FSA and 5ClSA were obtained for all eight conformers/isomers from density functional theory (DFT) (B3LYP) with 6-311++G(d,p) basis set calculations. The computational results identified the most stable conformer of 5-FSA and 5-ClSA as the C1 form. The complete assignments were performed on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. The spectroscopic and theoretical results were compared with the corresponding properties for 5-FSA and 5-ClSA monomers and dimer of C1 conformer. The optimized bond lengths, bond angles and calculated wavenumbers showed the best agreement with the experimental results. Copyright © 2010 John Wiley & Sons, Ltd.
TL;DR: The present work observed and characterized nine conformers of GABA using Fourier transform microwave spectroscopy in supersonic jets combined with laser ablation and confirmed the conformational richness of GABA.
Abstract: g-Aminobutyric acid (GABA) is arguably the most important inhibitory neurotransmitter in the brain and brainstem/spinal cord. Owing to the high torsional flexibility of its heavyatom backbone, this molecular system has a large number of low-energy conformers (see Figure 1). Identifying the stable conformers of GABA can be relevant to understanding the selectivity of the biological processes in which the neurotransmitter participates. This can be done by placing GABA on a supersonic jet such that conformers are cooled down and trapped in their energy minima. In such an isolated environment the conformers with sufficient population can be detected and studied by spectroscopic methods. In this context, several methods have made great contributions to the elucidation of the structures of biomolecules in the gas phase. In the present work we have observed and characterized nine conformers of GABA using Fourier transform microwave spectroscopy in supersonic jets combined with laser ablation. Microwave spectroscopy, considered the most definitive gas-phase structural probe, can distinguish between different conformational structures since they have unique moments of inertia and give separate rotational spectra. In general, large molecules, in particular those of biological importance, have low vapor pressures and tend to degrade upon heating, making them unsuited for structural studies in the gas phase. Recently, rotational studies of biomolecules have entered in a new stage with the LAMB-FTMW experiment, which combines laser ablation (LA) with molecular beam Fourier transform microwave spectroscopy (MB-FTMW), an approach that overcomes the problems of thermal decomposition associated with conventional heating methods. To date, different aand b-amino acids have been studied using this technique, making it possible to characterize their preferred conformations. Even in conformationally challenging systems these can be identified by rotational spectroscopy, as has been illustrated with the assignment of seven low-energy conformers of serine and threonine, six of cysteine, and four of b-alanine and proline. In the present work, we have examined the conformations of GABA. In this system the separation of the polar amino and carboxylic groups, characteristic of many families of neurotransmitters, opens new conformational possibilities with respect to a-amino acids if one considers the balance of intramolecular forces that contribute to stabilizing the different conformations. The five hindered rotations around the single bonds generate a plethora of conformational species (Figure 1). An overall picture of the conformational landscape obtained from theoretical predictions at the MP2/6-311++G(d,p) level confirms the conformational richness of GABA: the 30 feasible conformers shown in Figure 1 were localized with relative energies below 900 cm . These conformers are labeled by two letters (a, G, or g) followed by a number. The first letter refers to the configuration at Ca and the second one to the configuration at Cg : a means anti conformers, G gauche conformers with positive value of the torsional angle CCOOH-Ca-Cb-Cg or N-Cg-Cb-Ca, and g gauche conformers Figure 1. Predicted low-energy conformers of GABA. The nine observed conformers are circled.
TL;DR: Study of intra- and intermolecular hydrogen-bonding interaction and excited state proton transfer reaction in 4-hydroxyacridine and its hydrated clusters theoretically and under the provision of natural bond orbital and atoms in molecule analysis reveals that an intrinsic and two-water-molecule-assisted protonTransfer reaction in 5-HA is hindered by high energy barrier in the S(1) surface, whereas single- water-assisted PT reaction is practically rendered barrierless.
Abstract: Study of intra- and intermolecular hydrogen-bonding interaction and excited state proton transfer reaction has been carried out in 4-hydroxyacridine (4-HA) and its hydrated clusters theoretically. Density functional theory [B3LYP/6-311++G(d,p)] has been exploited to calculate structural parameters and relative energies of different conformers of 4-HA and its hydrates. The substantial impact of solvent reaction field on hydrogen-bond energies, conformational equilibrium, and tautomerization reaction in aqueous medium have been realized by employing Onsager and PCM reaction field methods, and the stability of the conformers of 4-HA is found to be profusely modulated by the electrostatic influence of the solvent. A deeper insight into the nature of H-bonding in 4-HA and its hydrated clusters has been achieved under the provision of natural bond orbital and atoms in molecule analysis. Elucidation of potential energy curves for proton transfer reaction reveals that an intrinsic and two-water-molecule-assisted ...
TL;DR: An atom–atom solvent exposure- and distance-dependent dielectric (SEDDD) function, which accounts for both electrostatic and dehydration energy components is proposed, which demonstrated a 20% increase in the success rate versus the best-performing DDD function.
Abstract: Physics-based force fields for ligand-protein docking usually determine electrostatic energy with distance-dependent dielectric (DDD) functions, which do not fully account for the dielectric permittivity variance between approximately 2 in the protein core and approximately 80 in bulk water. Here we propose an atom-atom solvent exposure- and distance-dependent dielectric (SEDDD) function, which accounts for both electrostatic and dehydration energy components. Docking was performed using the ZMM program, the AMBER force field, and precomputed libraries of ligand conformers. At the seeding stage, hundreds of thousands of positions and orientations of conformers from the libraries were sampled within the rigid protein. At the refinement stage, the ten lowest-energy structures from the seeding stage were Monte Carlo-minimized with the flexible ligand and flexible protein. A search was considered a success if the root mean square deviation (RMSD) of the ligand atoms in the apparent global minimum from the x-ray structure was <2 A. Calculations on an examining set of 60 ligand-protein complexes with different DDD functions and solvent-exclusion energy revealed outliers in most of which the ligand-binding site was located at the protein surface. Using a training set of 16 ligand-protein complexes, which did not overlap with the examining set, we parameterized the SEDDD function to minimize the RMSD of the apparent global minima from the x-ray structures. Recalculation of the examining set with the SEDDD function demonstrated a 20% increase in the success rate versus the best-performing DDD function.
TL;DR: Crystal polymorphism of the anti-diabetic drug Tolbutamide (TB) has been studied using various analytical techniques and several discrepancies in the published data on the structural and thermodynamic features of TB polymorphs are resolved.
TL;DR: It is shown that symmetric and chiral arrangements play a dominant role in the conformational landscape of the 18c6-alkali system.
Abstract: Crown ethers provide a valuable benchmark for the comprehension of molecular recognition mediated by inclusion complexes. One of the most relevant crown ethers, 18-crown-6 (18c6), features a flexible six-oxygen cyclic backbone that is well-known for its selective cation binding. This study employs infrared spectroscopy and quantum mechanical calculations to elucidate the structure of the gas-phase complexes formed by the 18c6 ether with the alkali metal cations. It is shown that symmetric and chiral arrangements play a dominant role in the conformational landscape of the 18c6−alkali system. Most stable 18c6−M+ conformers are found to have symmetries C 3v and C 2 for Cs+, D 3d for K+, C 1 and D 3d for Na+, and D 2 for Li+. Remarkably, whereas the bare 18c6 ether is achiral, chirality emerges in the C 2 and D 2 18c6−M+ conformations, both of which involve pairs of stable atropoisomers capable of acting as enantiomeric selective substrates.
TL;DR: Although all SDFs exhibit similar trends, [C(4)mim]I shows a reduced anion density facing the C(2)-H atoms of the cation and enhanced anion densities above and below the imidazolium ring plane, an effect that is stronger with smaller anions.
Abstract: The conformational isomerism of the 1-n-butyl-3-methylimidazolium cation, [C4mim]+, in halide-based ionic liquids—[C4mim]Cl, [C4mim]Br, and [C4mim]I—was explored by Raman spectroscopy. The [C4mim]+ cation exhibits trans−gauche conformational isomerism with respect to the N1−C7−C8−C9 dihedral angle of its butyl chain. The thermodynamics of trans−gauche conversion were analyzed through the successful evaluation of the corresponding Gibbs free energy, ΔisoG°, enthalpy, ΔisoH°, and entropy, ΔisoS°, of conformational isomerization. The values of ΔisoG° obtained are small (a few units of kJ/mol) and show a slight negative variation with the decrease of the size of the halide anion. On the other hand, ΔisoH° and ΔisoS° values are positive for [C4mim]I and decrease with the anion size to yield negative values for [C4mim]Cl and [C4mim]Br. This suggests that the negative electrostatic field around the halide anions stabilizes the gauche isomer from an enthalpic point of view. In order to study the structure and ion...
TL;DR: The state-of-the-art studies of the cellulose structure, major cellulose polymorphs, the crystal packing, conformers and hydrogen bond systems are analyzed based on publications of the last decade as mentioned in this paper.
Abstract: The state-of-the-art studies of the cellulose structure, major cellulose polymorphs, the crystal packing, conformers and hydrogen bond systems are analyzed based on publications of the last decade.
TL;DR: In this paper, the stability of the salt bridge (SB; zwitterionic) conformer relative to the most stable canonical structure with a single formal charge site (charge solvation; CS) of aliphatic amino acids (e.g., Pro, Na+, K+, Rb+, and Cs+) was investigated using IRMPD spectroscopy utilizing light generated by a free electron laser and computational modeling.
TL;DR: In the presence of secondary phosphine oxide (2 equiv), PtCl2(cod) was converted to a series of cis/trans platinum complexes with PAs as ligands.
TL;DR: The first generation and spectroscopic identification of the higher-lying E conformer of the simplest aromatic carboxylic acid, benzoic acid (1a), as its O-deuterated isotopologue (E)-d(1)-1a using matrix-isolation techniques and the first Hammett relationships for atom tunneling are derived.
Abstract: We present the first generation and spectroscopic identification of the higher-lying E conformer of the simplest aromatic carboxylic acid, benzoic acid (1a), as its O-deuterated isotopologue (E)-d1...
TL;DR: In this article, the PF6 salts of 5-benzyl-1-isopropylidene- and 5-(1)-methylimidazolidinones with various substituents in the 2-position have been prepared, and single crystals suitable for X-ray structure determination have been obtained of 14 compounds, i.e., 2-10 and 12-16 (rigs.
Abstract: The PF6 salts of 5-benzyl-1-isopropylidene- and 5-benzyl-1-cinnamylidene-3-methylimidazolidin-4-ones 1 (Scheme) with various substituents in the 2-position have been prepared, and single crystals suitable for X-ray structure determination have been obtained of 14 such compounds, i.e., 2-10 and 12-16 (rigs. 2-5). In nine of the structures, the Ph ring of the benzyl group resides above the heterocycle. in contact with the cis-substituent at C(2) (staggered conformation A: Figs. 1-3); in three structures, the Ph ring lies above the iminium pi-plane (staggered conformation B; Figs. 1 and 4); in two structures, the benzylic C-C bond has an eclipsing conformation (C; Figs. 1 and 5) which places the Ph ring simultaneously at a maximum distance with its neighbors, the CO group, the N=C-pi-system, and the cis-substituent at C(2) oft lie heterocycle. It is suggested by a qualitative conformational analysis (Fig. 6) that the three staggered conformations of the benzylic C-C bond are all subject to unfavorable steric interactions, so that the eclipsing conformation may lie a kind of 'escape'. State-of-the-art quantum-chemical methods, with large AO basic sets (near the limit) for the single-point calculations, were used to compute the structures of seven of the 14 iminium ions, i.e., 3, 4/12, 5-7, 13, and 16 (Table) in the two staggered conformations, A and B, with the benzylic Ph group above the ring and above the iminium pi-system, respectively. In all cases, the more stable Computed conformer ('isolated-molecule' structure) corresponds to the one present in the crystal (overlay in rig. 7). The energy differences are small (<= 2 kcal/mol) which, together with the result of a potential-curve calculation for the rotation around the benzylic C-C bond of one of the structures, 16 (Fig. 8), suggests that the benzyl group is more or less freely rotating at ambident temperatures. The importance of intramolecular London dispersion (benzene ring in 'contact' with the cis-substituent in conformation A) for DFT and other quantum-chemical computations is demonstrated; the benzyl-imidazolidinones 1 appear to be ideal systems for detecting dispersion contributions between a benzene ring and alkyl or aryl CH groups. Enylidene ions of the type studied herein are the reactive intermediates of enantioselective organocatalytic conjugate additions, Diels-Alder reactions, and many other transformations involving alpha,beta-unsaturated carbonyl compounds. Our experimental and theoretical results are discussed in view of the performance of 5-benzyl-imidazolidinones as enantioselective catalysts.
TL;DR: The aim of this work was to determine Raman descriptors for the lateral packing, the conformation, and the structure of ceramides III, IIIA, and IIIB issued from the same phytosphingosine ceramide and only presenting differences in the number of double bonds in the hydrocarbon chains.
Abstract: The barrier function of the stratum corneum (SC) is directly related to: (1) the nature and the composition of the lipids in the intercellular spaces and (2) the conformational order of the ceramides within this layer. The aim of this work was to determine Raman descriptors for the lateral packing, the conformation, and the structure of ceramides III, IIIA, and IIIB issued from the same phytosphingosine ceramide and only presenting differences in the number of double bonds in the hydrocarbon chains. Temperature was used as a variable parameter in order to access the different states of the conformational order and supramolecular organization of the three ceramides, and Raman spectra were collected at each temperature. By using a high-resolution Raman spectrometer and working on a spectral range going from 400 to 3,200 cm(-1), we were able to assess simultaneously the different descriptors of structure and organization, i.e., the methyl rocking bands (840-910 cm(-1)) for the chain-end conformers, the C-C skeletal stretching (1,060-1,130 cm(-1)), and the CH stretching region (2,800-3,050 cm(-1)) for the trans and gauche conformations, the CH(2) scissoring bands to follow the changes in the lateral packing, and finally the amide I band to evaluate the state of the H-bonds between the polar and head groups.
TL;DR: The gas-phase structures of alkali-metal cation complexes of the amino acid methionine (Met) as well as protonated methionines are investigated using infrared multiple photon dissociation (IRMPD) spectroscopy utilizing light generated by a free electron laser.
Abstract: The gas-phase structures of alkali-metal cation complexes of the amino acid methionine (Met) as well as protonated methionine are investigated using infrared multiple photon dissociation (IRMPD) spectroscopy utilizing light generated by a free electron laser. Spectra of Li+(Met) and Na+(Met) are similar and relatively simple, whereas the spectra of K+(Met), Rb+(Met), and Cs+(Met) include distinctive new bands. Measured IRMPD spectra are compared to spectra calculated at the B3LYP/6-311+G(d,p) level of theory to identify the conformations present in the experimental studies. For Li+ and Na+ complexes, the only conformation present is a charge-solvated, tridentate structure that binds the metal cation to the amine and carbonyl groups of the amino acid backbone and the sulfur atom of the side chain, [N,CO,S]. In addition to the [N,CO,S] conformer, bands corresponding to alkali-metal cation binding to a bidentate zwitterionic structure, [CO2−], are clearly present for the K+, Rb+, and Cs+ complexes. Theoretical calculations of the lowest energy conformations of Rb+ and Cs+ complexes suggest that the experimental spectra could also include contributions from two additional charge-solvated structures, tridentate [COOH,S] and bidentate [COOH]. For H+(Met), the IRMPD action spectrum is reproduced by multiple low-energy [N,CO,S] conformers, in which the protonated amine group hydrogen bonds to the carbonyl oxygen atom and the sulfur atom of the amino acid side chain. These [N,CO,S] conformers only differ in their side-chain orientations.
TL;DR: It is shown that to employ SDSL to uniquely identify conformational equilibria is possible based on the time scale for exchange of the nitroxide between distinct environments that give rise to multicomponent EPR spectra, and the exchange rate constants between substates with lifetimes of approximately 1–70 μs can be estimated by the approach.
Abstract: The function of many proteins involves equilibria between conformational substates, and to elucidate mechanisms of function it is essential to have experimental tools to detect the presence of conformational substates and to determine the time scale of exchange between them. Site-directed spin labeling (SDSL) has the potential to serve this purpose. In proteins containing a nitroxide side chain (R1), multicomponent electron paramagnetic resonance (EPR) spectra can arise either from equilibria involving different conformational substates or rotamers of R1. To employ SDSL to uniquely identify conformational equilibria, it is thus essential to distinguish between these origins of multicomponent spectra. Here we show that this is possible based on the time scale for exchange of the nitroxide between distinct environments that give rise to multicomponent EPR spectra; rotamer exchange for R1 lies in the ≈0.1–1 μs range, while conformational exchange is at least an order of magnitude slower. The time scales of exchange events are determined by saturation recovery EPR, and in favorable cases, the exchange rate constants between substates with lifetimes of approximately 1–70 μs can be estimated by the approach.