Racemic Structure Research Articles

Designing a square periodic racemic helix photonic metamaterial using phase-controlled interference lithography for tailored chiral response

In this study, we propose a double exposure phase-controlled laser interference lithography (DE-PCLIL) approach in 4 + 1 beams interference to design a three-dimensional (3D) racemic helical periodic nanostructure. The explicit azimuthal rotation of each beam by π/2 between the two exposures and the resultant intensity distribution discover the racemic 3D helix structure arranged in the square unit cell. The proof of concept is experimentally demonstrated by recording a series of cross-sectional images at different z-planes of the volumetric interference pattern on a CMOS camera using a spatial light modulator (SLM). Additionally, we propose an approach to realize tapering in such a geometry through a slight variation of the interference angle in both exposures. We numerically investigated optical modes and circular dichroism (CD) characteristics of the racemic helix metamaterial. The racemic helix metamaterial structure offers an angle of incidence and polarization-insensitive coupled mode. Through numerical studies, we propose an alternative way to bring 3.4-fold CD signal enhancement by varying the phase of a particular handed helix only through modulating the local chiral field. Such 3D structure is profound with perfect absorption in broad spectral regions, potentially suited for plasmonic absorber-based photovoltaic and photo-catalysis applications.

Novel antiferroelectric materials with resorcinol-based symmetrical fluorinated bent-core mesogens

The synthesis of several symmetrical bent-core compounds with two or four fluorine atoms as substituents on the calamitic units is reported. The influence of fluorine substitution concerning its effect upon the mesophase structure and switching behavior was investigated. The synthesized compounds are built from resorcinol as central core and contain seven phenyl rings linked by ester, imine and azo units with terminal decyloxy/dodecyloxy chains. The mesophases were characterized by polarizing optical microscopy, differential scanning calorimetry, electro-optical investigations and X-ray diffraction (XRD) studies. The photochemical characterisation of bent-core azobenzene compounds confirmed the structure of E isomer. The temperature range of mesophases increases upon the introduction of fluorine substituents, as compared with the corresponding unsubstituted compound. All the compounds exhibit antiferroelectric properties. Depending on the number of the F substituents, racemic SmCSPA mixtures and SmCAPA homochiral structures were identified. High values of spontaneous polarization up to 900 nC/cm2 were recorded. DFT studies were used to calculate the minimum energy molecular structures, the dipole moments and the electrostatic potential surfaces of the compounds.

Racemic crystal structures of A-DNA duplexes.

The ease with which racemic mixtures crystallize compared with the equivalent chiral systems is routinely taken advantage of to produce crystals of small molecules. However, biological macromolecules such as DNA and proteins are naturally chiral, and thus the limited range of chiral space groups available hampers the crystallization of such molecules. Inspiring work over the past 15 years has shown that racemic mixtures of proteins, which were made possible by impressive advances in protein chemical synthesis, can indeed improve the success rate of protein crystallization experiments. More recently, the racemic crystallization approach was extended to include nucleic acids as a possible aid in the determination of enantiopure DNA crystal structures. Here, findings are reported that suggest that the benefits may extend beyond this. Two racemic crystal structures of the DNA sequence d(CCCGGG) are described which were found to fold into A-form DNA. This form differs from the Z-form DNA conformation adopted by the chiral equivalent in the solid state, suggesting that the use of racemates may also favour the emergence of new conformations. Importantly, the racemic mixture forms interactions in the solid state that differ from the chiral equivalent (including the formation of racemic pseudo-helices), suggesting that the use of racemic DNA mixtures could provide new possibilities for the design of precise self-assembled nanomaterials and nanostructures.

Additive-assisted preferential crystallization of racemic component: A case of norvaline

Herein, we report a successful resolution of L-norvaline, a racemic compound system, performed near the eutectic composition by coupling preferential crystallization with tailor-made additives. The structures of enantiomer and racemate were characterized by PXRD, DSC, and the enantiomeric purity were measured by Chiral HPLC. The preferential crystallization process was designed and established from binary melting phase diagram and ternary solution phase diagram. The effects of supersaturation, solution enantiomer composition, and seed quantity on the preferential crystallization process were investigated. However, the significant improvements of enantiomeric purity and product yield were demonstrated by additive-assisted preferential crystallization approach using tailor-made additives. These additives bearing similar structure motifs to norvaline a highly selective binding to the racemate rather than enantiomer and remarkably suppress nucleation of DL-norvaline, the key factor determining the resultant enantiomer purity and separation efficiency. The underly inhibition principle was revealed due to the centrosymmetric packing of the racemate while the polarity of enantiomer leads to only partial or slight crystallization suppression. The interesting inhibition mode by tailor-made additives is also believed to be applicable for other racemic crystallization systems. Our established additive-assisted preferential crystallization has showed great potential in the development of separation technology and resolution of enantiomer from racemic compounds.

Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging.

Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. (R)-[18F]13 was identified through the preliminary evaluation of two carbon-11-labeled racemic structures [11C]11 and [11C]16. In dynamic positron-emission tomography (PET) scans, (R)-[18F]13 showed a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain. High brain uptake and brain-to-blood ratio were achieved by (R)-[18F]13 in comparison with previously reported reversible MAGL PET radiotracers. Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of (R)-[18F]13 accumulation in the mouse brain. These findings indicate that (R)-[18F]13 ([18F]YH149) is a highly promising PET probe for visualizing MAGL non-invasively in vivo and holds great potential to support drug development.

Racemized photonic crystals for physical unclonable function.

As Internet of Things-based technologies continue to digitalize our society, the development of secure and robust identification systems against evolving adversaries remains a grave challenge. Recently, physical unclonable functions (PUFs) have garnered tremendous scientific interest due to their intrinsic randomness, which makes them difficult to counterfeit. Herein, we present a facile approach for fabricating optical PUFs using spontaneous mirror symmetry breaking of molecular self-assembly. The PUF composed of racemic helical structures that generate chiroptical signals exhibits high encoding capacity (∼1013 000), precise recognition rate, and impressive reconfigurability. The present study demonstrates that the utilization of random symmetry breaking is a promising approach to the design of high-level security systems.

Water-Induced Chiral Separation on a Au(111) Surface.

Facing the scientific question of the origin of chirality in life, water is considered to play a crucial role in driving many biologically relevant processes in vivo. Water has been demonstrated in vitro to be related to chiral generation, amplification, and inversion, while the underlying mechanism is still not fully understood. Real-space evidence at the single-molecule level is thus urgently required to understand the role of water molecules in biomolecular chirality related issues. Herein, we choose one of the RNA bases, the biomolecule uracil (U), which self-assembles into racemic hydrogen-bonded structures. Upon water exposure, surprisingly, racemic structures could be transformed to homochiral water-involved structures, resulting in an unexpected chiral separation on the surface. The origin of chiral separation is due to preferential binding between water and the specific site of U molecules, which leads to the formation of the energetically most favorable homochiral (U-H2O-U)2 cluster as seed for subsequent chiral amplification. Such a water-driven self-assembly process may also be extended to other biologically relevant systems such as amino acids and sugars, which would provide general insights into the role that water molecules may play in the origin of homochirality in vivo.

Bis-Argentivorous Molecules Bridged by Phenyl and 4,4'-Biphenyl Groups: Structural and Dynamic Behavior of Silver Complexes.

Bis-argentivorous molecules (La and Lb), which have phenyl and 4,4'-biphenyl groups as linkers, have been prepared. The structures of Ag+ complexes with the new ligands (La and Lb) were investigated in solution and the solid state. The CSI-MS and 1H NMR titration of La and Lb with Ag+ show 1:1 and 1:2 complexes depending on the [Ag+]:[L] ratios. In the solid-state structures, single crystals of La and Lb with 2 equiv of Ag+ were prepared. X-ray crystallography of the silver(I) complexes with La and Lb showed that an intramolecular racemic structure (Δ(δδδδ)Λ(λλλλ) form) and a racemic mixture of Δ(δδδδ)Δ(δδδδ) and Λ(λλλλ)Λ(λλλλ) forms were formed, respectively. The dynamic 1H NMR studies suggest the following: (i) the activation entropies (ΔS⧧) of the side arm rotations in the Ag+ complex with La were all negative, indicating restricted rotation of the side arms due to their shortness, and (ii) the ΔS⧧ values of the Ag+ complexes with Lb were negative only when the side arms of both cyclens rotated simultaneously, and the ΔS⧧ values for the 1:1 and 1:2 complexes were positive when one cyclen side arm was rotated. These values of ΔS⧧ indicate that the biphenyl side arms between the two cyclens are not long enough to rotate the ring freely.

Access to Enantiomeric Organic Compounds with Potential for Synthesis via Racemic Conglomerates: Inositol Derivatives as a Case in Point

The crystal structure database was used to identify inositol derivatives that could be crystallizing as racemic conglomerates. Among the six racemic inositol derivatives identified, racemic 4-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate (A) was found to be a true conglomerate and was resolved on the multigram scale by the preferential crystallization technique. This resolution procedure does not require the use of any enantiomeric resolving agent. The resolved enantiomers of A are useful for the synthesis of natural and unnatural enantiomeric derivatives of inositol, since they carry orthogonal hydroxy protecting groups. Racemic 4-O-methanesulfonyl-myo-inositol-1,3,5-orthoformate (B) on crystallization from common organic solvents generally yielded racemic twin crystals, while in the presence of structural analogs as additives, they yielded true racemic crystals. A comparison of the crystal structures of the true racemate, twinned crystal and crystal of one of the enantiomers of B, revealed the reasons for the formation of polymorphic (twin) crystals. Such instances are relatively rarely encountered but nevertheless shed light on our understanding of polymorphism and twinning of crystals.

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution.

The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to preorganize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies to predict and design conformational and binding properties of macrocycles as functional scaffolds for peptidomimetics. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has a higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.

Frontispiece: Aggregation and Amyloidogenicity of the Nuclear Coactivator Binding Domain of CREB‐Binding Protein

Aggregation and self-assembly of nuclear coactivator binding domain of CREB-binding protein was studied under different experimental conditions. Single l- or d-enantiomers fold into left- or right-handed helical structures at neutral pH while β-sheet amyloid arrangement occurs under acidic conditions. Mixtures of both enantiomers promote self-assembly into amyloid β-sheet structures highlighting the role of chirality in the formation of thermodynamically more stable racemic β-sheet structures. Fore more information, see the Full Paper by V. Torbeev et al. on page 9889 ff.

Aggregation and Amyloidogenicity of the Nuclear Coactivator Binding Domain of CREB-Binding Protein.

The nuclear coactivator binding domain (NCBD) of transcriptional co-regulator CREB-binding protein (CBP) is an example of conformationally malleable proteins that can bind to structurally unrelated protein targets and adopt distinct folds in the respective protein complexes. Here, we show that the folding landscape of NCBD contains an alternative pathway that results in protein aggregation and self-assembly into amyloid fibers. The initial steps of such protein misfolding are driven by intermolecular interactions of its N-terminal α-helix bringing multiple NCBD molecules into contact. These oligomers then undergo slow but progressive interconversion into β-sheet-containing aggregates. To reveal the concealed aggregation potential of NCBD we used a chemically synthesized mirror-image d-NCBD form. The addition of d-NCBD promoted self-assembly into amyloid precipitates presumably due to formation of thermodynamically more stable racemic β-sheet structures. The unexpected aggregation of NCBD needs to be taken into consideration given the multitude of protein-protein interactions and resulting biological functions mediated by CBP.

Polymorphism at the Metal/Organic Interface: Hybrid Phase with Alternating Coplanar and Vertical Adsorption Geometry

Polymorphism of organic molecular materials plays a prominent role in organic (opto)electronic devices, where the structural properties of metal/organic interfaces determine performance-critical parameters such as charge carrier injection rates. Here, we show that (sub)monolayers of a 2D-prochiral aromatic dinitrile with a bent quaterphenyl backbone engage in pronounced polymorphism on a Ag(111) surface and form a unique phase with alternating polar orientation of the molecules. In the saturated monolayer, the molecules are nearly coplanar with the substrate (flat-lying) and form an ordered racemic structure consisting of chiral dimers stabilized by H···NC hydrogen bonds. At submonolayer coverages, two ordered phases coexist with a dilute mobile phase. One phase forms homochiral domains with a quasi-Kagome structure. The other phase has a unique structure consisting of alternating rows of flat-lying and upright-standing molecules. The two different polar orientations can be distinguished by scanning tunneling microscopy. The upright-standing molecules have a straight and brighter shape and show increased packing density compared to their flat-lying counterparts. These results reveal the great local variability of molecular arrangements at metal/organic interfaces, even for fixed global parameters such as temperature and coverage.

Crystallization of chiral molecular compounds: what can be learned from the Cambridge Structural Database?

A detailed study on chiral compound structures found in the Cambridge Structural Database (CSD) is presented. Solvates, salts and co-crystals have intentionally been excluded, in order to focus on the most basic structures of single enantiomers, scalemates and racemates. Similarity between the latter and structures of achiral monomolecular compounds has been established and utilized to arrive at important conclusions about crystallization of chiral compounds. For example, the fundamental phenomenon of conglomerate formation and, in particular, their frequency of occurrence is addressed. In addition, rarely occurring kryptoracemates and scalemic compounds (anomalous racemates) are discussed. Finally, an extended search of enantiomer solid solutions in the CSD is performed to show that there are up to 1800 instances most probably hiding among the deposited crystal structures, while only a couple of dozen have been previously known and studied.

Kryptoracemic compound hunting and frequency in the Cambridge Structural Database

Determination of kryptoracemic compound frequency in the Cambridge Structural Database using CCDC Python API script.

Retention of Native Quaternary Structure in Racemic Melittin Crystals.

Racemic crystallography has been used to elucidate the secondary and tertiary structures of peptides and small proteins that are recalcitrant to conventional crystallization. It is unclear, however, whether racemic crystallography can capture native quaternary structure, which could be disrupted by heterochiral associations. We are exploring the use of racemic crystallography to characterize the self-assembly behavior of membrane-associated peptides, very few of which have been crystallized. We report a racemic crystal structure of the membrane-active peptide melittin; the new structure allows comparison with a previously reported crystal structure of L-melittin. The tetrameric assembly observed in crystalline L-melittin has been proposed to represent the tetrameric state detected in solution for this peptide. This tetrameric assembly is precisely reproduced in the racemic crystal, which strengthens the conclusion that the tetramer is biologically relevant. More broadly, these findings suggest that racemic crystallography can provide insight on native quaternary structure.

Homochiral and racemic MicroED structures of a peptide repeat from the ice-nucleation protein InaZ.

The ice-nucleation protein InaZ from Pseudomonas syringae contains a large number of degenerate repeats that span more than a quarter of its sequence and include the segment GSTSTA. Ab initio structures of this repeat segment, resolved to 1.1 Å by microfocus X-ray crystallography and to 0.9 Å by the cryo-EM method MicroED, were determined from both racemic and homochiral crystals. The benefits of racemic protein crystals for structure determination by MicroED were evaluated and it was confirmed that the phase restriction introduced by crystal centrosymmetry increases the number of successful trials during the ab initio phasing of the electron diffraction data. Both homochiral and racemic GSTSTA form amyloid-like protofibrils with labile, corrugated antiparallel β-sheets that mate face to back. The racemic GSTSTA protofibril represents a new class of amyloid assembly in which all-left-handed sheets mate with their all-right-handed counterparts. This determination of racemic amyloid assemblies by MicroED reveals complex amyloid architectures and illustrates the racemic advantage in macromolecular crystallography, now with submicrometre-sized crystals.

In Silico Prediction of Structural Properties of a Racemic Porous Organic Cage Crystal

Porous organic cage (POC) solids are porous materials made up of individual porous molecules held together by noncovalent forces. Although many examples of POCs have been made in homochiral forms (i.e., crystals in which every molecule has the same chirality), crystallization of POCs that contain mixtures of chiral molecules can also yield useful properties. For instance, our previous work has demonstrated that a POC crystal [cage crystal 3 (CC3)-racemic] synthesized using a racemic mixture of diaminocyclohexane has improved sorption properties and stability than a similar POC crystal synthesized with homochiral diaminocyclohexane. The key aim of this paper is to predict the structure of CC3-racemic with atomic detail because it is challenging to fully resolve the structure of this racemic crystal experimentally since only subtle differences exist between the racemic structure and the known crystal structure of homochiral CC3. Here, we introduce an in silico prediction method that combines electronic stru...

Racemic crystal structures of peptide toxins, GsMTx4 prepared by protein total synthesis.

The Piezo channel is a versatile mechanosensitive cation channel that mediates tactile, vascular development, and proprioception. GsMTx4 is the only reported inhibitor specifically targeting Piezo channels. Although the sequence of GsMTx4 is reported, the crystal structure of GsMTx4 is still unknown. Here, we achieved the two-segment synthesis of GsMTx4 and its enantiomer, enGsMTx4, through hydrazide based Native Chemical Ligation, and analyzed the crystal structure of GsMTx4 through the racemic crystallization technology. By analyzing the structure, we found that there is a hydrophobic patch surrounded by aromatic residues and charged residues.

Racemic X-ray structure of L-type calcium channel antagonist Calciseptine prepared by total chemical synthesis

Snake toxin Calciseptine as a natural antagonist of L-type calcium channel has potential drug values, but its structural information remains unknown. Here, we report the total chemical synthesis of Calciseptine by using hydrazide based native chemical ligation. The crystal structure of Calciseptine was determined by racemic protein crystallography technique. Compared to the structure of its homologous family protein, we found that Calciseptine is adopting a typical three-finger structure.