Similar Conformations Research Articles

ClickGen: Directed exploration of synthesizable chemical space via modular reactions and reinforcement learning

Despite the significant potential of generative models, low synthesizability of many generated molecules limits their real-world applications. In response to this issue, we develop ClickGen, a deep learning model that utilizes modular reactions like click chemistry to assemble molecules and incorporates reinforcement learning along with inpainting technique to ensure that the proposed molecules display high diversity, novelty and strong binding tendency. ClickGen demonstrates superior performance over the other reaction-based generative models in terms of novelty, synthesizability, and docking conformation similarity for existing binders targeting the three proteins. We then proceeded to conduct wet-lab validation on the ClickGen’s proposed molecules for poly adenosine diphosphate-ribose polymerase 1. Due to the guaranteed high synthesizability and model-generated synthetic routes for reference, we successfully produced and tested the bioactivity of these novel compounds in just 20 days, much faster than typically expected time frame when handling sufficiently novel molecules. In bioactivity assays, two lead compounds demonstrated superior anti-proliferative efficacy against cancer cell lines, low toxicity, and nanomolar-level inhibitory activity to PARP1. We demonstrate that ClickGen and related models may represent a new paradigm in molecular generation, bringing AI-driven, automated experimentation and closed-loop molecular design closer to realization.

Revealing 5-(3,5-difluorobenzyl)-1H-indazole as the active pharmacophore of ALK/ROS1 dual inhibitors through theoretical calculations and biological activity evaluations

Anaplastic lymphoma kinase (ALK) and tyrosine protein kinase (ROS1) are recognized as driver genes in lung cancer, with dual inhibition of both targets offering a promising approach to enhance therapeutic outcomes in non-small cell lung cancer (NSCLC). Although numerous ALK/ROS1 inhibitors have received FDA approval, detailed research into the essential active structural motifs within these inhibitors remains limited. Addressing this gap, the current study employed computer-aided drug design (CADD) methodologies, incorporating bioisosteric and conformational similarity principles to design and synthesize 31 dual-target 2-morpholinobenzamide derivatives. These derivatives each include the 5-(3,5-difluorobenzyl)-1H-indazole, 4-benzylmorpholine, and thiophene moieties. Based on docking binding energies, we proposed that 5-(3,5-difluorobenzyl)-1H-indazole may represent a key pharmacophore for ALK/ROS1 activity. Subsequent kinase and cellular assays validated this hypothesis, with compound X4 exhibiting optimal inhibitory activity against both ALK and ROS1 kinases and lung cancer cell lines, achieving IC50 values of 0.512 µM (ALK), 0.766 µM (ROS1), and 0.034 ± 0.002 µM (H2228). In vitro antitumor assays demonstrated dose-dependent induction of apoptosis in H2228 cells by X4. Western blot (WB) analysis further confirmed that X4 effectively suppresses the expression of p-ALK and p-ERK. Importantly, X4 exhibited high specificity in targeting ALK and ROS1 across a range of kinases. In an H2228 xenograft model, X4 achieved a tumor inhibition rate of 54.71 %, underscoring its considerable potential in ALK/ROS1 inhibition.

Roles of ZEB1 and ZEB2 in E-cadherin expression and cell aggressiveness in head and neck cancer.

Zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in cancer cell differentiation and metastasis, and has been well studied in the field of cancer cell biology. ZEB2 has a highly similar conformation to ZEB1, but its role in head and neck squamous cell carcinoma (HNSCC) cells is not fully understood. Here, we separately overexpressed ZEB1 and ZEB2 in C57BL/6 mouse oral cancer (MOC) cells and investigated their cellular characteristics, including E-cadherin levels, motile properties, chemoresistance, and metastatic ability in immunocompetent mice. Both ZEB1 and ZEB2 overexpression reduced epithelial traits and converted cells to an aggressive phenotype. Surprisingly, ZEB1 overexpression increased the endogenous level of ZEB2 in MOC cells, and vice versa. The molecular mechanisms underlying these findings remain unclear. However, the in vitro anchorage-independent growth of MOC cells overexpressing ZEB2 was considerably greater than that of MOC cells overexpressing ZEB1. These findings suggest that ZEB2, like ZEB1, has the ability to induce the differentiation of cancer cells into those with highly aggressive traits.

Discovery of Substituted 5-(2-Hydroxybenzoyl)-2-Pyridone Analogues as Inhibitors of the Human Caf1/CNOT7 Ribonuclease.

The Caf1/CNOT7 nuclease is a catalytic component of the Ccr4-Not deadenylase complex, which is a key regulator of post-transcriptional gene regulation. In addition to providing catalytic activity, Caf1/CNOT7 and its paralogue Caf1/CNOT8 also contribute a structural function by mediating interactions between the large, non-catalytic subunit CNOT1, which forms the backbone of the Ccr4-Not complex and the second nuclease subunit Ccr4 (CNOT6/CNOT6L). To facilitate investigations into the role of Caf1/CNOT7 in gene regulation, we aimed to discover and develop non-nucleoside inhibitors of the enzyme. Here, we disclose that the tri-substituted 2-pyridone compound 5-(5-bromo-2-hydroxy-benzoyl)-1-(4-chloro-2-methoxy-5-methyl-phenyl)-2-oxo-pyridine-3-carbonitrile is an inhibitor of the Caf1/CNOT7 nuclease. Using a fluorescence-based nuclease assay, the activity of 16 structural analogues was determined, which predominantly explored substituents on the 1-phenyl group. While no compound with higher potency was identified among this set of structural analogues, the lowest potency was observed with the analogue lacking substituents on the 1-phenyl group. This indicates that substituents on the 1-phenyl group contribute significantly to binding. To identify possible binding modes of the inhibitors, molecular docking was carried out. This analysis suggested that the binding modes of the five most potent inhibitors may display similar conformations upon binding active site residues. Possible interactions include π-π interactions with His225, hydrogen bonding with the backbone of Phe43 and Van der Waals interactions with His225, Leu209, Leu112 and Leu115.

A multi-center study on genetic variations in the fusion protein of respiratory syncytial virus from children with Acute Lower Respiratory Tract Infections in China during 2017–2021

Respiratory syncytial virus (RSV) is a significant cause of acute lower respiratory tract infection (ALRTI) in children under five years of age. Between 2017 and 2021, 396 complete sequences of the RSV F gene were obtained from 500 RSV-positive throat swabs collected from ten hospitals across nine provinces in China. In addition, 151 sequences from China were sourced from GenBank and GISAID, making a total of 549 RSV F gene sequences subjected to analysis. Phylogenetic and genetic diversity analyses revealed that the RSV F genes circulating in China from 2017 to 2021 have remained relatively conserved, although some amino acids (AAs) have undergone changes. AA mutations with frequencies ≥ 10% were identified at six sites and the p27 region: V384I (site I), N276S (site II), R213S (site Ø), and K124N (p27) for RSV A; F45L (site I), M152I/L172Q/S173 ​L/I185V/K191R (site V), and R202Q/I206M/Q209R (site Ø) for RSV B. Comparing mutational frequencies in RSV-F before and after 2020 revealed minor changes for RSV A, while the K191R, I206M, and Q209R frequencies increased by over 10% in RSV B. Notably, the nirsevimab-resistant mutation, S211N in RSV B, increased in frequency from 0% to 1.15%. Both representative strains aligned with the predicted RSV-F structures of their respective prototypes exhibited similar conformations, with low root-mean-square deviation values. These results could provide foundational data from China for the development of RSV mAbs and vaccines.

Redox-Active Conopeptide Li520 Has Evolved to Catalyze Oxidative Folding of Conotoxins.

The evolution of miniature conopeptide Li520 (COWC*, *: C-terminal amidation) to exhibit the disulfide isomerase activity was probed using structure, function, disulfide conformation, and the precursor gene sequence. The peptides Li520, Li504, [O2A]Li520, [W3A]Li520, and Grx506, homologues active-site motif of glutaredoxin, were chemically synthesized and assessed for their disulfide reduction potential, intrinsic folding of disulfides, and disulfide isomerization activity on α-conotoxin ImI. The reduction potential of the disulfide of peptides varies from -189 to -344 mV, which is within the range observed for the redox family of proteins that modulates the folding of protein disulfides. The oxidative folding studies confirm the significance of the tryptophan residue in engaging Li520 in disulfide-exchange reactions and the role of proline hydroxylation in extending the lifetime of Li520 in a reduced free thiol state. Studies of quenching of tryptophan fluorescence by the disulfide in situ folding reaction in conjunction with the optimized structures by density functional theory (DFT) confirm the difference in conformation of disulfides between the native and mutant peptides. Interestingly, the native peptide Li520/Li504 shares a similar disulfide conformation of (-,-)AntiRHHook with the redox family of proteins known to modulate disulfides, particularly in lieu of the tetrapeptide of glutaredoxin, deviating from its disulfide conformation compared to its naive protein. Analysis of the precursor gene sequences of M-superfamily conotoxins revealed the presence of Li520 in different cone snail species with distinct food habits and possible modes of evolution through the diversification of cysteine motifs. The results of the report suggest that the short redox conopeptide Li520 has evolved to facilitate the oxidative folding of conotoxins and may be useful to develop as reagents for the synthesis of therapeutically important cysteine-rich peptides.

MultiModRLBP: A Deep Learning Approach for Multi-Modal RNA-Small Molecule Ligand Binding Sites Prediction.

This study aims to tackle the intricate challenge of predicting RNA-small molecule binding sites to explore the potential value in the field of RNA drug targets. To address this challenge, we propose the MultiModRLBP method, which integrates multi-modal features using deep learning algorithms. These features include 3D structural properties at the nucleotide base level of the RNA molecule, relational graphs based on overall RNA structure, and rich RNA semantic information. In our investigation, we gathered 851 interactions between RNA and small molecule ligand from the RNAglib dataset and RLBind training set. Unlike conventional training sets, this collection broadened its scope by including RNA complexes that have the same RNA sequence but change their respective binding sites due to structural differences or the presence of different ligands. This enhancement enables the MultiModRLBP model to more accurately capture subtle changes at the structural level, ultimately improving its ability to discern nuances among similar RNA conformations. Furthermore, we evaluated MultiModRLBP on two classic test sets, Test18 and Test3, highlighting its performance disparities on small molecules based on metal and non-metal ions. Additionally, we conducted a structural sensitivity analysis on specific complex categories, considering RNA instances with varying degrees of structural changes and whether they share the same ligands. The research results indicate that MultiModRLBP outperforms the current state-of-the-art methods on multiple classic test sets, particularly excelling in predicting binding sites for non-metal ions and instances where the binding sites are widely distributed along the sequence. MultiModRLBP also can be used as a potential tool when the RNA structure is perturbed or the RNA experimental tertiary structure is not available. Most importantly, MultiModRLBP exhibits the capability to distinguish binding characteristics of RNA that are structurally diverse yet exhibit sequence similarity. These advancements hold promise in reducing the costs associated with the development of RNA-targeted drugs.

Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine.

Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae: this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB5), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (Oδ-H → Fδ-) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB5 with native GM1, the GM1 carbohydrate epitope, and meta-mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions.

In vivo photocontrol of orexin receptors with a nanomolar light-regulated analogue of orexin-B

Orexinergic neurons are critically involved in regulating arousal, wakefulness, and appetite. Their dysfunction has been associated with sleeping disorders, and non-peptide drugs are currently being developed to treat insomnia and narcolepsy. Yet, no light-regulated agents are available to reversibly control their activity. To meet this need, a photoswitchable peptide analogue of the endogenous neuroexcitatory peptide orexin-B was designed, synthesized, and tested in vitro and in vivo. This compound – photorexin – is the first photo-reversible ligand reported for orexin receptors. It allows dynamic control of activity in vitro (including almost the same efficacy as orexin-B, high nanomolar potency, and subtype selectivity to human OX2 receptors) and in vivo in zebrafish larvae by direct application in water. Photorexin induces dose- and light-dependent changes in locomotion and a reduction in the successive induction reflex that is associated with sleep behavior. Molecular dynamics calculations indicate that trans and cis photorexin adopt similar bent conformations and that the only discriminant between their structures and activities is the positioning of the N-terminus. This, in the case of the more active trans isomer, points towards the OX2 N-terminus and extra-cellular loop 2, a region of the receptor known to be involved in ligand binding and recognition consistent with a “message-address” system. Thus, our approach could be extended to several important families of endogenous peptides, such as endothelins, nociceptin, and dynorphins among others, that bind to their cognate receptors through a similar mechanism: a “message” domain involved in receptor activation and signal transduction, and an “address” sequence for receptor occupation and improved binding affinity.

Multi-institutional investigation into the robustness of intra-cranial multi-target stereotactic radiosurgery plans to patient setup errors

PurposeThis study aimed to analyse correlations between planning factors including plan geometry and plan complexity with robustness to patient setup errors. MethodsMultiple-target brain stereotactic radiosurgery (SRS) plans were obtained through the Trans-Tasman Radiation Oncology Group (TROG) international treatment planning challenge (2018). The challenge dataset consisted of five intra-cranial targets with a 20 Gy prescription. Setup error was simulated using an in-house tool. Dose to targets was assessed via dose covering 99 % (D99 %) of gross tumour volume (GTV) and 98 % of planning target volume (PTV). Dose to organs at risk was assessed using volume of normal brain receiving 12 Gy and maximum dose covering 0.03 cc of brainstem. Plan complexity was assessed via edge metric, modulation complexity score, mean multi-leaf collimator (MLC) gap, mean MLC speed and plan modulation. ResultsEven for small (0.5 mm/°) errors, GTV D99 % was reduced by up to 20 %. The strongest correlation was found between lower complexity plans (larger mean MLC gap and lower edge metric) and higher robustness to setup error. Lower complexity plans had 1 %–20 % fewer targets/scenarios with GTV D99 % falling below the specified tolerance threshold. These complexity metrics correlated with 100 % isodose volume sphericity and dose conformity, though similar conformity was achievable with a range of complexities. ConclusionsA higher level of importance should be directed towards plan complexity when considering plan robustness. It is recommended when planning multi-target SRS, larger MLC gaps and lower MLC aperture irregularity be considered during plan optimisation due to higher robustness should patient positioning errors occur.

Conformations of influenza A M2 protein in DOPC/DOPS and E. coli native lipids and proteins

We compared the conformations of the transmembrane domain (TMD) of influenza A M2 (IM2) protein reconstituted in 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPC/DOPS) bilayers to those in isolated Escherichia coli (E. coli) membranes, having preserved its native proteins and lipids. IM2 is a single-pass transmembrane protein known to assemble into a homo-tetrameric proton channel. To represent this channel, we made a construct containing the IM2’s TMD region flanked by the juxtamembrane residues. The single cysteine substitution, L43C, of leucine located in the bilayer polar region was paramagnetically tagged with a methanethiosulfonate nitroxide label for the electron spin resonance (ESR) study. For this particular residue, we probed the conformations of the spin-labeled IM2 reconstituted in DOPC/DOPS and isolated E. coli membranes using continuous-wave ESR and double electron-electron resonance (DEER) spectroscopy. The total protein-to-lipid molar ratio spanned the range from 1:230 to 1:10,400. The continuous-wave ESR spectra corresponded to very slow spin-label motion in both environments. In all cases, the DEER data were reconstructed into distance distributions with well-resolved peaks at 1.68 and 2.37 nm in distance and amplitude ratios of 1.41 ± 0.2 and 2:1, respectively. This suggests four nitroxide spin labels located at the corners of a square, indicative of an axially symmetric tetramer. The distance modeling of DEER data with molecular modeling software applied to the NMR molecular structures (PDB: 2L0J) confirmed the symmetry and closed state of the C-terminal exit pore of the IM2 TMD tetramer in agreement with the model. Thus, we can conclude that, under conditions of pH 7.4 used in this study, IM2 TMD has similar conformations in model lipid bilayers and membranes made of native E. coli lipids and proteins of comparable thickness and fluidity, notwithstanding the complexity of the E. coli membranes caused by their lipid diversity and the abundance of integral and peripheral membrane proteins.

Unexpected Stress Overshoot in Extensional Flow of Star Polymer Melts.

Previous studies have shown that the nonlinear rheological behavior of 3-arm star polymer melts in fast extensional flow is identical to that of linear polymers with the same span molecular weight, because the star polymers are highly aligned and have a similar conformation as the corresponding linear polymers. However, with more arms, it would be more difficult for the stars to be aligned like linear chains, and the nonlinear extensional rheology of star polymers with more arms under large deformations has not been investigated yet. Here we show that the star polystyrene (8-10 arms) melts behave differently from the linear polystyrenes. A transient stress overshoot is observed in the fast extensional flow, probably due to the difference in entanglement density near and far away from the branch point.

Design and synthesis of 6-C-alkyl-DMDP type nanomolar inhibitors of β-galactosidase and β-glucosidase based on broussonetine S and related derivatives

Broussonetine S (9), its C-1′ and C-10′ stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10′ epimer (10′-epi-9) were nanomolar inhibitors of bovine liver β-galactosidase and β-glucosidase; while their C-1′ stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1′ hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver β-glucosidase and β-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of β-glucosidase or β-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of β-glucosidase and β-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower β-glucosidase and β-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of β-galactosidase and β-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.

ELECTRONIC PARAMETERS OF CONFORMATIONAL STATES OF ABETA-AMYLOID PEPTIDE (25-35)

ELECTRONIC PARAMETERS OF CONFORMATIONAL STATES OF ABETA-AMYLOID PEPTIDE (25-35)

In silico energetic and molecular dynamic simulations studies demonstrate potential effect of the point mutations with implications for protein engineering in BDNF

Protein engineering by directed evolution is time-consuming. Hence, in silico techniques like FoldX-Yasara for ∆∆G calculation, and SNPeffect for predicting propensity for aggregation, amyloid formation, and chaperone binding are employed to design proteins. Here, we used in silico techniques to engineer BDNF-NTF3 interaction and validated it using mutations with known functional implications for NGF dimer. The structures of three mutants representing a positive, negative, or neutral ∆∆G involving two interface residues in BDNF and two mutations representing a neutral and positive ∆∆G in NGF, which is aligned with BDNF, were selected for molecular dynamics (MD) simulation. Our MD results conclude that the secondary structure of individual protomers of the positive and negative mutants displayed a similar or different conformation from the NTF3 monomer, respectively. The positive mutants showed fewer hydrophobic interactions and higher hydrogen bonds compared to the wild-type, negative, and neutral mutants with similar SASA, suggesting solvent-mediated disruption of hydrogen-bonded interactions. Similar results were obtained for mutations with known functional implications for NGF and BDNF. The results suggest that mutations with known effects in homologous proteins could help in validation, and in silico directed evolution experiments could be a viable alternative to the experimental technique used for protein engineering.

Characterizing the Conformational Dynamics of Human SUMO2: Insights into its Interaction with Metal Ions and SIMs.

SUMO (Small Ubiquitin-like Modifiers) proteins are involved in a crucial post-translational modification commonly termed as SUMOylation. In this work, we have investigated the native-state conformational flexibility of human SUMO2 and its interaction with Cu2+ and Zn2+ ions using 15N-1H based 2D NMR spectroscopy. After SUMO1, SUMO2 is the most studied SUMO isoform in humans which shares 45 % and ~80 % similarity with SUMO1 in terms of sequence and structure, respectively. In this manuscript, we demonstrate that compared to SUMO1, several amino acids around the α1-helix region of SUMO2 access energetically similar near-native conformations. These conformations could play a crucial role in SUMO2's non-covalent interactions with SUMO interaction motifs (SIMs) on other proteins. The C-terminal of SUMO2 was found to bind strongly with Cu2+ ions resulting in a trimeric structure as observed by gel electrophoresis. This interaction seems to interfere in its non-covalent interaction with a V/I-x-V/I-V/I based SIM in Daxx protein.

Artificial Fingertip with Embedded Fiber-Shaped Sensing Arrays for High Resolution Tactile Sensing.

Replication of the human sense of touch would be highly advantageous for robots or prostheses as it would allow an agile and dexterous interaction with the environment. The article presents an approach for the integration of a micro-electromechanical system sensing skin with 144 tactile sensors on a soft, human-sized artificial fingertip. The sensing technology consists of thin, 1D sensing strips which are wrapped around the soft and curved fingertip. The sensing strips include 0.5 mm diameter capacitive sensors which measure touch, vibrations, and strain at a resolution of 1 sensor/mm2. The method allows to leverage the advantages of sensing skins over other tactile sensing technologies while showing a solution to integrate such skins on a soft three-dimensional body. The adaptable sensing characteristics are dominated by the thickness of a spray coated silicone layer, encapsulating the sensors in a sturdy material. We characterized the static and dynamic sensing capabilities of the encapsulated taxels up to skin thicknesses of 600 μm. Taxels with 600 μm skin layers have a sensitivity of 6 fF/mN, corresponding to an ∼5 times higher sensitivity than a human finger if combined with the developed electronics. They can detect vibrations in the full tested range of 0-600 Hz. The softness of a human finger was measured to build an artificial sensing finger of similar conformity. Miniaturized readout electronics allow the readout of the full finger with 220 Hz, which enables the observation of touch and slipping events on the artificial finger, as well as the estimation of the contact force. Slipping events can be observed as vibrations registered by single sensors, whereas the contact force can be extracted by averaging sensor array readouts. We verified the sturdiness of the sensing technology by testing single coated sensors on a chip, as well as the completely integrated sensing fingertip by applying 15 N for 10,000 times. Qualitative datasets show the response of the fingertip to the touch of various objects. The focus of this article is the development of the sensing hardware and the basic characterization of the sensing performance.

Benzoyl Valine Quasiracemates: Pairing CF3 Quasienantiomers with H to t-Butyl.

Understanding the interplay of structural features responsible for molecular assembly is essential for molecular crystal engineering. When assembling molecules with encoded motifs, first choice supramolecular strategies almost always include robust directional nonbonded contacts. Quasiracemic materials, considered near racemates since cocrystallization occurs with chemically unique components, lack a molecular framework or functional group restrictions, highlighting the importance of molecular shape to molecular assembly. Recently, our group reported quasiracemates derived from benzoyl leucine/phenylalanine derivatives with two points of chemical difference. In this study, we modified the chemical framework with valine and increased the scope of the work by imposing a larger variance in the side chain substituents. Pairing a CF3 component with quasienantiomers that differ iteratively from hydrogen to t-butyl offers an important view into the supramolecular landscape of these materials. Single-crystal X-ray crystallography and lattice energy assessments, coupled with conformational and crystal structure similarity searches, show an elevated degree of isomorphism for many of the targeted 17 racemates and quasiracemates. These benzoyl amino acid molecular architectures create extended hydrogen-bond patterns in the crystal that provide enhanced opportunities to study the shape space and molecular recognition profiles for a diverse family of quasienantiomeric components.

Synthesis and Crystal Structures of Rhomb-Shaped Dimeric Pd(II) Complexes with Arylethynyl-Substituted 2,2′-Bipyridine through CH⋯π Interactions in the Crystalline States

Two molecular structures of a complex C26H16Cl2N2Pd (1) with a benzene hemisolvate (1•0.5C6H6) and a complex C34H20Cl2N2Pd (2) revealed similar conformations: one side of the arylethynyl group is flat to the bipyridine plane while the other side of the arylethynyl group is highly twisted to the plane because rhomb-like dimer fragments are formed between respective two complexes through CH⋯π interactions. The Hirshfeld surface analysis indicates that the most important contributions for the crystal packing of 1 are from H⋯H (33.6%), C⋯H/H⋯C (28.3%), Cl⋯H/H⋯Cl (17.8%), and C⋯C (10.6%) interactions and those of 2 are from H⋯H (36.5%), C⋯H/H⋯C (26.0%), Cl⋯H/H⋯Cl (15.7%), and C⋯C (12.3%) interactions, indicating the remarkable CH⋯π and electron distribution of molecules by Cl ions. The benzene solvate molecule of 1•0.5C6H6 performs to fill the internal space instead of the naphthyl group. Detailed crystallographic and DFT studies were performed to understand the molecular structures and the corresponding supramolecular associations.

Noble Metal Nanoparticles with Nanogel Coatings: Coinage Metal Thiolate-Stabilized Glutathione Hydrogel Shells.

Developing biocompatible nanocoatings is crucial for biomedical applications. Noble metal colloidal nanoparticles with biomolecular shells are thought to combine diverse chemical and optothermal functionalities with biocompatibility. Herein, we present nanoparticles with peptide hydrogel shells that feature an unusual combination of properties: the metal core possesses localized plasmon resonance, whereas a few-nanometer-thick shells open opportunities to employ their soft framework for loading and scaffolding. We demonstrate this concept with gold and silver nanoparticles capped by glutathione peptides stacked into parallel β-sheets as they aggregate on the surface. A key role in the formation of the ordered structure is played by coinage metal(I) thiolates, i.e., Ag(I), Cu(I), and Au(I). The shell thickness can be controlled via the concentration of either metal ions or peptides. Theoretical modeling of the shell's molecular structure suggests that the thiolates have a similar conformation for all the metals and that the parallel β-sheet-like structure is a kinetic product of the peptide aggregation. Using third-order nonlinear two-dimensional infrared spectroscopy, we revealed that the ordered secondary structure is similar to the bulk hydrogels of the coinage metal thiolates of glutathione, which also consist of aggregated stacked parallel β-sheets. We expect that nanoparticles with hydrogel shells will be useful additions to the nanomaterial toolbox. The present method of nanogel coating can be applied to arbitrary surfaces where the initial deposition of the seed glutathione monolayer is possible.