Solution-state Structure Research Articles

The Role of Nitrogen Donors in Zinc Catalysts for Lactide Ring-Opening Polymerization.

The electronic effects of nitrogen donors in zinc catalysts for ring-opening polymerization of cyclic esters were investigated. Alkyl and benzyloxy zinc complexes supported by tridentate diamino- and aminoimino phenolate ligands were synthesized, and their solid-state and solution structures characterized. The solution-state structures showed that the alkyl complexes are mononuclear, while the alkoxy complexes are dimeric with the ligands coordinated with different denticities depending on the nature of the ligand donors. The catalytic activities of these compounds toward the ring-opening polymerization of racemic lactide were studied and showed that catalysts with secondary and imine nitrogen donors are more active than analogues with tertiary amines.

Tautomerism of 2-(pyridine-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one

The work deals with both solution state (using 1H, 13C and 15N NMR) and solid state (using X-ray) structure of 2-(pyridine-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one. The compound exists in the solution predominantly as 5-oxo tautomer where the amount of 4-oxo form depends on the solvent used. Mutual interconversion between the tautomers is slow on the NMR time scale and is studied by means of both EXSY and variable temperature NMR. In the solid state, the compound is solely as 5-oxo tautomer.

Reactivity of alkynylsilanes towards B-halogeno-1,3,2-diselenaborolanes with an annelated dicarba-closo-dodecaborane(12) unit

Abstract The C≡C bond of alkynylsilanes undergoes 1,2-haloboration with 2-halogeno-1,3,2-diselenaborolano-4,5-[1,2-dicarba-closo-dodecaborane(12)], in competition with reversible insertion into one of the B–Se bonds (selenoboration) to afford a seven-membered ring and finally, by elimination of Me3Si–X (X = Cl, Br, I), the corresponding B-alkynyl derivatives. The reactions were monitored by NMR spectroscopy (11B, 13C, 29Si and 77Se NMR). The proposed solution-state structures are also supported by DFT calculations of single molecule geometries and NMR parameters [B3LYP/6-311 + G(d,p) level of theory].

Solution-State Structure and Affinities of Cyclodextrin:Fentanyl Complexes by Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulation.

Cyclodextrins (CDs) are investigated for their ability to form inclusion complexes with the analgesic fentanyl and three similar molecules: acetylfentanyl, thiofentanyl, and acetylthiofentanyl. Stoichiometry, binding strength, and complex structure are revealed through nuclear magnetic resonance (NMR) techniques and discussed in terms of molecular dynamics (MD) simulations. It was found that β-cyclodextrin is generally capable of forming the strongest complexes with the fentanyl panel. Two-dimensional NMR data and computational chemical calculations are used to derive solution-state structures of the complexes. Binding of the fentanyls to the CDs occurs at the amide phenyl ring, leaving the majority of the molecule solvated by water, an observation common to all four fentanyls. This finding suggests a universal binding behavior, as the vast majority of previously synthesized fentanyl analogues contain this structural moiety. This baseline study serves as the most complete work on CD:fentanyl complexes to date and provides the insights into strategies for producing future generations of designer cyclodextrins capable of stronger and more selective complexation of fentanyl and its analogues.

Addressing a "Black Box" of Bottom-Up Synthesis: Revealing the Structures of Growing Colloidal-Nanocrystal Nuclei.

In bottom-up synthesis, products from reactions of structural building units rapidly pass from soluble molecular complexes to nanoscale intermediates, whose solution-state structures defy elucidation by any routine method. To address this, electron diffraction is used to reveal the structures of cryogenically "trapped" colloidal nanocrystals.

ChemInform Abstract: Limitations and Extensions of the Lock‐and‐Key Principle: Differences Between Gas State, Solution and Solid State Structures

AbstractReview: 124 refs.

Diffusion Coefficient-Formula Weight (D-FW) Analysis of (2)H Diffusion-Ordered NMR Spectroscopy (DOSY).

We report extension of the D-FW analysis using referenced (2)H DOSY. This technique was developed in response to limitations due to peak overlay in (1)H DOSY spectra. We find a corresponding linear relationship (R(2) > 0.99) between log D and log FW as the basis of the D-FW analysis. The solution-state structure of THF solvated lithium diisopropyl amide (LDA) in hydrocarbon solvent was chosen to demonstrate the reliability of the methodology. We observe an equilibrium between monosolvated and disolvated dimeric LDA complexes at room temperature. Additionally we demonstrate the application of the (2)H D-FW analysis using a compound with an exchangeable proton that is readily labeled with (2)H. Hence, the (2)H DOSY D-FW analysis is shown to provide results consistent with the (1)H DOSY method, thereby greatly extending the applicability of the D-FW analysis.

Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication

Herpesviruses require a nuclear egress complex (NEC) for efficient transit of nucleocapsids from the nucleus to the cytoplasm. The NEC orchestrates multiple steps during herpesvirus nuclear egress, including disruption of nuclear lamina and particle budding through the inner nuclear membrane. In the important human pathogen human cytomegalovirus (HCMV), this complex consists of nuclear membrane protein UL50, and nucleoplasmic protein UL53, which is recruited to the nuclear membrane through its interaction with UL50. Here, we present an NMR-determined solution-state structure of the murine CMV homolog of UL50 (M50; residues 1-168) with a strikingly intricate protein fold that is matched by no other known protein folds in its entirety. Using NMR methods, we mapped the interaction of M50 with a highly conserved UL53-derived peptide, corresponding to a segment that is required for heterodimerization. The UL53 peptide binding site mapped onto an M50 surface groove, which harbors a large cavity. Point mutations of UL50 residues corresponding to surface residues in the characterized M50 heterodimerization interface substantially decreased UL50-UL53 binding in vitro, eliminated UL50-UL53 colocalization, prevented disruption of nuclear lamina, and halted productive virus replication in HCMV-infected cells. Our results provide detailed structural information on a key protein-protein interaction involved in nuclear egress and suggest that NEC subunit interactions can be an attractive drug target.

Limitations and extensions of the lock-and-key principle: differences between gas state, solution and solid state structures.

The lock-and-key concept is discussed with respect to necessary extensions. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Stereoelectronic effects due to lone pair orientation can lead to variation of binding constants by orders of magnitude. Hydrophobic interactions due to high-energy water inside cavities modify the mechanical lock-and-key picture. That optimal affinities are observed if the cavity is only partially filled by the ligand can be in conflict with the lock-and-key principle. In crystals other forces than those between host and guest often dominate, leading to differences between solid state and solution structures. This is exemplified in particular with calixarene complexes, which by X-ray analysis more often than other hosts show guest molecules outside their cavity. In view of this the particular problems with the identification of weak interactions in crystals is discussed.

Molecular Simulation of Conformational Pre-Organization in Cyclic RGD Peptides.

To test the ability of molecular simulations to accurately predict the solution-state conformational properties of peptidomimetics, we examined a test set of 18 cyclic RGD peptides selected from the literature, including the anticancer drug candidate cilengitide, whose favorable binding affinity to integrin has been ascribed to its pre-organization in solution. For each design, we performed all-atom replica-exchange molecular dynamics simulations over several microseconds and compared the results to extensive published NMR data. We find excellent agreement with experimental NOE distance restraints, suggesting that molecular simulation can be a useful tool for the computational design of pre-organized solution-state structure. Moreover, our analysis of conformational populations estimates that, despite the potential for increased flexibility due to backbone amide isomerizaton, N-methylation provides about 0.5 kcal/mol of reduced conformational entropy to cyclic RGD peptides. The combination of pre-organization and binding-site compatibility explains the strong binding affinity of cilengitide to integrin.

ChemInform Abstract: Natalamycin A, an Ansamycin from a Termite‐Associated Streptomyces sp.

We report a preliminary functional and complete structural characterization of a highly unusual geldanamycin analog, natalamycin A, that was isolated from Streptomyces strain M56 recovered from a South African nest of Macrotermes natalensis termites. Bioassay-guided fractionation based on antifungal activity led to the isolation of natalamycin A, and a combination of NMR spectroscopy and X-ray crystallographic analysis, including highly-accurate quantum-chemical NMR calculations on the largest and most conformationally-flexible system to date, revealed natalamycin A's three-dimensional solid- and solution-state structure. This structure along with the structures of related compounds isolated from the same source suggest a geldanamycin-like biosynthetic pathway with unusual post-PKS modifications.

ChemInform Abstract: The Palladium(II) Complex of N,N‐Diethyl‐1‐ferrocenyl‐3‐thiabutanamine: Synthesis, Solution and Solid State Structure and Catalytic Activity in Suzuki—Miyaura Reaction.

AbstractThe title complex generated in situ is an excellent catalyst in Suzuki—Miyaura coupling.

Characterization of Peptides Designed to Control Crystal Nucleation and Growth

Organisms, from algae to humans are known to mold complex, hierarchical hard tissues from minerals using biomolecular templates and additives. Molecular-level mechanistic understanding of how these biomolecules, particularly proteins, participate in the nucleation and growth of these inorganic crystals has been a longstanding goal. We design peptides with transformative abilities over calcite crystals using Rosetta. Based on the theory of how additives alter crystal nucleation and growth, we employ four modification strategies to modify the morphology of the crystal, viz. a peptide binding to a face, an array of peptides binding to a face, peptides pinning steps and peptides blocking kinks. To test the designs, we employ a variety of techniques ranging from measurements at the atomic scale to full crystal observations. We also investigate alternative mechanisms of modification by comparing the interactions predicted by Rosetta in other select states to those in the target state. For each design, we obtain the solution-state structure of the peptide by circular dichroism. To test peptides designed against a non-native face of calcite, we artificially stabilize the face for binding measurements. The overall crystal morphology change is then tested by incubating supersaturated precursor solutions with the design peptides. To confirm the predicted mechanism of growth alternation, we observe the change in kinetics of calcite step growth with peptide doping using in situ AFM, and report calcite step velocities. Finally, by nucleating calcite on a monolayer of the designed peptides, we examine the face on which calcite nucleated and compare it to our target face. These experimental results provide a feedback loop to the next generation of designs and enable the rational design of bio-surface interactions.

Small molecule binding to a G-hairpin and a G-triplex: a new insight into anticancer drug design targeting G-rich regions.

To gain new insights into G-quadruplex-drug interactions, we captured the solution-state structures of the complexes between a drug-like small molecule and a G-hairpin/G-triplex. Our results indicated that the ligand initially binds to the intermediates and induces stepwise folding into a quadruplex.

1,2-Hydroboration and 1,1-Carboboration of Alkynyl(ferrocenyl)vinylsilanes. Novel Siloles

Abstract Alkynyl(ferrocenyl)vinylsilanes containing up to three alkynyl units were prepared and treated with 9-borabicyclo[3.3.1]nonane (9-BBN). All reactions proceeded in the beginning by regioselective 1,2-hydroboration of the vinyl group, with boron attached to the terminal carbon. This was followed by intra-molecular 1,1-carboboration, leading to fused silacarbacycles, depending on the number of C≡C bonds. Thus, new siloles and even fused siloles became available. The solution-state structures were revealed by multinuclear NMR techniques (1H, 11B, 13C, 29Si NMR), complemented by calculated single-molecule structures and calculated NMR parameters at the B3LYP/6-311+G(d,p) level of theory. In one case, the solid-state structure of a bicyclic derivative was determined.

Native mass spectrometry: towards high-throughput structural proteomics.

Native mass spectrometry (MS) has become a sensitive method for structural proteomics, allowing practitioners to gain insight into protein self-assembly, including stoichiometry and three-dimensional architecture, as well as complementary thermodynamic and kinetic aspects. Although MS is typically performed in vacuum, a body of literature has described how native solution-state structure is largely retained on the timescale of the experiment. Native MS offers the benefit that it requires substantially smaller quantities of a sample than traditional structural techniques such as NMR and X-ray crystallography, and is therefore well suited to high-throughput studies. Here we first describe the native MS approach and outline the structural proteomic data that it can deliver. We then provide practical details of experiments to examine the structural and dynamic properties of protein assemblies, highlighting potential pitfalls as well as principles of best practice.

Self-assembly of self-assembled molecular triangles

A rare variety of self-assembled molecular triangle [Pd3(bpy)3(imidazolate)3](NO3)3, 1 is prepared by the combination of Pd(bpy)(NO3)2 with imidazole, at 1:1 ratio, in acetonitrile-water. Deprotonation of imidazole happened during the course of the complexation reaction where upon the metallomacrocycle is formed. The bowl-shaped trinuclear architecture of 1 is crafted with three peripheral bpy units capable of π−π stacking interactions. While the solution state structure of 1can be best described as a trinuclear complex, in the solid-state well-fashioned intermolecular π−π and CH- π interactions are observed. Thus, in the solid-state further self-assembly of already self-assembled molecular triangle is witnessed. The triangular panels are arranged in a linear manner utilizing intermolecular π−π interactions where upon two out of three bpy units of each molecule participated in the chain formation.

In Depth Study on Solution-State Structure of Poly(lactic acid) by Vibrational Circular Dichroism

Polyesters are biodegradable analogues of polypeptides, but their biochemical applications have been hampered by the lack of a method to analyze polyester conformation in a solution state. We have demonstrated that vibrational circular dichroism (VCD) spectroscopy can conveniently and accurately elucidate the conformation of polyesters through the studies on poly(l-lactic acid) (PLLA), PLLA-amylose complex, and oligo(l-lactic acid). The analysis of VCD exciton couplet of these molecules has clarified the stable left-handed helical structure of PLLA, while density functional theory calculations of oligo(l-lactic acid) have revealed its detailed structural nature.

Natalamycin A, an Ansamycin from a Termite-Associated Streptomyces sp.

We report a preliminary functional and complete structural characterization of a highly unusual geldanamycin analog, natalamycin A, that was isolated from Streptomyces strain M56 recovered from a South African nest of Macrotermes natalensis termites. Bioassay-guided fractionation based on antifungal activity led to the isolation of natalamycin A, and a combination of NMR spectroscopy and X-ray crystallographic analysis, including highly-accurate quantum-chemical NMR calculations on the largest and most conformationally-flexible system to date, revealed natalamycin A's three-dimensional solid- and solution-state structure. This structure along with the structures of related compounds isolated from the same source suggest a geldanamycin-like biosynthetic pathway with unusual post-PKS modifications.

Methylene-linked anilide-bis(aryloxide) ligands: lithium, sodium, potassium, chromium(III), and vanadium(III) ligation.

The anilide-bis(aryloxide) proligands H3[ONO(R)] (where H3[ONO(R)] = 2,6-(3-R(1)-5-R(2)-2-hydroxybenzyl)-4-tert-butyl-N-tolyl-aniline; H3[ONO(tBu)], R(1) = (t)Bu, R(2) = Me; H3[ONO(Me)], R(1) = Me, R(2) = (t)Bu; H3[ONO(Me2)], R(1) = R(2) = Me) were synthesized from 2-bromo-5-tert-butyl-isophthalic acid dimethyl ester in three steps in multigram scale. The ligand precursor H3[ONO(tBu)] was readily doubly and triply deprotonated with alkali metal reagents to generate the related derivatives M2[H(ONO(tBu))] and M3[ONO(tBu)] (M = Li, Na, K). The extent of ligand deprotonation is observed to depend on the choice of deprotonating reagents and solvents. Transmetalation reaction of the trilithium derivative Li3[ONO(tBu)] with MCl3(THF)3 (M = Cr, V; THF = tetrahydrofuran) afforded [(ONO(tBu))CrCl(THF){Li(THF)}] (5) and [(ONO(tBu))V(THF)] (6). The vanadium complex 6 reacted readily with 2-butyne, styrene oxide, and mesityl azide, yielding [(ONO(tBu))V(η(2)-MeCCMe)] (7), [(ONO(tBu))V(O)] (8), and [(ONO(tBu))V(NMes)] (9), respectively. The solid-state structures of H3[ONO(tBu)] and metal complexes were determined by X-ray crystallography. The [ONO(tBu)] ligand adopts a u-shaped structure in solution and solid state.