The Effect of Hyperconjugation and Hydrogen Bonding on the Conformers of Methylated Monosaccharides.

The conformational landscapes of four 1-O-methylated monosaccharides-methyl a-glucose, methyl b-glucose, methyl a-galactose, and methyl b-galactose-were characterized using jet-cooled broadband rotational spectroscopy, supported by density functional theory calculations. A newly designed, simple pulsed nozzle assembly was used to introduced the sugar samples into a jet expansion without thermal degradation, eliminating the need for a complex and expensive laser ablation system. Ten conformers were experimentally identified by assigning their rotational spectra, and the intricate methyl internal rotation splittings were analysed. Notably, methylation alters the directionality of intramolecular hydrogen bonding of a-galactose highlighting its impact on structural preference. Natural bond orbital, intrinsic bond strength, and non-covalent interaction analyses were conducted to explore the interplay between hydrogen bonding and hyperconjugation. A set of σ to σ* neutral hyperconjugative interactions were found to override a strong hydrogen bond, driving a preference for the gauche conformers.

Single-Luminophore Molecular Engineering for Rapidly Phototunable Solid-State Luminescence.

Smart materials enabling emission intensity or wavelength tuning by light stimulus attract attention in numerous cutting-edge fields. However, due to the generally dense molecular stacking against photoresponsivity in solid states, especially in crystals, developing rapidly phototunable solid-state luminescent systems remains challenging. Herein, we propose a new luminophore that serves as both a photoresponsive unit and a luminescent group, while possessing enhanced conformational freedom to provide a solution. Namely, photoexcitation-induced molecular conformational change of an ionized persulfurated arene based on weak intermolecular aliphatic C-H···π interaction was employed. On these basis, rapidly enhanced phosphorescence upon irradiation can be observed in a series of phase states, like solution state, crystal, and amorphous state, especially with a high photoresponsive rate of 0.033 s-1 in crystal state that is superior to the relevant reported cases. Moreover, a rapidly phototunable afterglow effect is achieved by extending this molecule into some polymer-based doping systems, endowing the system with unique dynamic imaging and fast photopatterning capabilities. Such a single-luminophore molecular engineering and the underlying mechanism have implications for building different condensed functional materials, principally for those with stimuli responses in solid states.

Controlling the Helical Pitch of Foldamers Through Terminal Functionality: A Solid State Study.

Developing new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho-azobenzene/2,6-pyridyldicarboamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.4 Å to 7.3 Å). Additionally, crystallographic analysis of a library ten foldamers has identified general trends in the influence of a range of terminal functionalities, including carboxylbenzyl (Cbz), diphenylcarbamyl (N(Ph)2), ferrocene (Fc) and tert-butyloxycarbonyl (Boc), in controlling the folding behaviour of these supramolecular scaffolds. These studies could prove useful in the future development of functional foldamers which adopt specific sizes and shapes.

Dual, Photo-Responsive and Redox-Active Supramolecular Foldamers.

We report on dual, light-responsive and redox-active foldamers that demonstrate reversible and robust stimuli-induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light- and redox-driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non-irradiative and oxidative/reductive conditions. This proof-of-concept work paves the way towards the creation of novel stimuli-responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli.

Unlocking the power of AI models: exploring protein folding prediction through comparative analysis.

Protein structure determination has made progress with the aid of deep learning models, enabling the prediction of protein folding from protein sequences. However, obtaining accurate predictions becomes essential in certain cases where the protein structure remains undescribed. This is particularly challenging when dealing with rare, diverse structures and complex sample preparation. Different metrics assess prediction reliability and offer insights into result strength, providing a comprehensive understanding of protein structure by combining different models. In a previous study, two proteins named ARM58 and ARM56 were investigated. These proteins contain four domains of unknown function and are present in Leishmania spp. ARM refers to an antimony resistance marker. The study's main objective is to assess the accuracy of the model's predictions, thereby providing insights into the complexities and supporting metrics underlying these findings. The analysis also extends to the comparison of predictions obtained from other species and organisms. Notably, one of these proteins shares an ortholog with Trypanosoma cruzi and Trypanosoma brucei, leading further significance to our analysis. This attempt underscored the importance of evaluating the diverse outputs from deep learning models, facilitating comparisons across different organisms and proteins. This becomes particularly pertinent in cases where no previous structural information is available.

Temperature-Induced Sign Inversion of Circularly Polarized Luminescence of Binaphthyl-Bridged Tetrathiapyrenophanes.

D2-symmetric (R)-binaphthyl-bridged pyrenophanes containing thioether bonds were synthesized. The pyrenophanes exhibited the temperature-induced sign inversion of circularly polarized luminescence (CPL) while maintaining the emission wavelength and reversibility. The Δglum value reached 0.02, and the FL quenching by heat was negligible. The sign inversion of CPL originates from the inversion of intramolecular excimer chirality associated with excitation dynamics. The two pyrenes form a kinetically trapped left-handed twist excimer at low temperatures, while they form a thermodynamically favored right-handed twist excimer at high temperatures. The thioether linkers can impart flexibility suitable for the inversion of chirality of the excimers.

Cytogenetics in the management of hematological malignancies: An overview of alternative technologies for cytogenetic characterization.

Genomic characterization is an essential part of the clinical management of hematological malignancies for diagnostic, prognostic and therapeutic purposes. Although CBA and FISH are still the gold standard in hematology for the detection of CNA and SV, some alternative technologies are intended to complement their deficiencies or even replace them in the more or less near future. In this article, we provide a technological overview of these alternatives. CMA is the historical and well established technique for the high-resolution detection of CNA. For SV detection, there are emerging techniques based on the study of chromatin conformation and more established ones such as RTMLPA for the detection of fusion transcripts and RNA-seq to reveal the molecular consequences of SV. Comprehensive techniques that detect both CNA and SV are the most interesting because they provide all the information in a single examination. Among these, OGM is a promising emerging higher-solution technique that offers a complete solution at a contained cost, at the expense of a relatively low throughput per machine. WGS remains the most adaptable solution, with long-read approaches enabling very high-resolution detection of CAs, but requiring a heavy bioinformatics installation and at a still high cost. However, the development of high-resolution genome-wide detection techniques for CAs allows for a much better description of chromoanagenesis. Therefore, we have included in this review an update on the various existing mechanisms and their consequences and implications, especially prognostic, in hematological malignancies.

Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space.

An ab initio conformational analysis of oral beyond Rule of 5 (bRo5) drugs was complemented with measured permeability and logP(octanol) to derive design principles conferring oral bioavailability. 3D polar surface area (PSA) thresholds for oral bRo5 drugs coincided with those reported for Ro5 space. The majority of oral bRo5 drugs exceeded the Ro5 logP threshold of 5, reflecting a bias for permeability. Above 500 Da molecular weight (MW), oral drugs and highly permeable Novartis compounds occupy a narrow polarity range (topological or TPSA/MW) of 0.1-0.3 Å2 /Da, whose upper half coincides with the lower 90 percentiles of the Novartis logP set. This TPSA/MW range and 3D PSA below 100 Å2 define the "Rule of ~1 /5" for balancing lipophilicity and permeability. Neutral TPSA, defined as TPSA minus 3D PSA occurs independent of conformation, intramolecular hydrogen bonds (IMHB) and MW, suggesting it is an intrinsic molecular property. Neutral TPSA increased in the lead optimization (LO) campaigns of three first in class de novo designed bRo5 drugs and may be a useful design parameter in bRo5 space.

Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds.

The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.

The Fluorescent Enzyme Cascade Detects Low Abundance Protein Modifications Suitable for the Assembly of Functionally Annotated Modificatome Databases.

Pathophysiological functions of proteins critically depend on both their chemical composition, including post-translational modifications, and their three-dimensional structure, commonly referred to as structure-activity relationship. Current analytical methods, like capillary electrophoresis or mass spectrometry, suffer from limitations, such as the detection of unexpected modifications at low abundance and their insensitivity to conformational changes. Building on previous enzyme-based analytical methods, we here introduce a fluorescence-based enzyme cascade (fEC), which can detect diverse chemical and conformational variations in protein samples and assemble them into digital databases. Together with complementary analytical methods an automated fEC analysis established unique modification-function relationships, which can be expanded to a proteome-wide scale, i. e. a functionally annotated modificatome. The fEC offers diverse applications, including hypersensitive biomarker detection in complex samples.

The Use of Bridging Ligand Substituents to Bias the Population of Localized and Delocalized Mixed-Valence Conformers in Solution.

The electronic structure and associated spectroscopic properties of ligand-bridged, bimetallic 'mixed-valence' complexes of the general form {M}(µ-B){M+ } are dictated by the electronic couplings, and hence orbital overlaps, between the metal centers mediated by the bridge. In the case of complexes such as [{Cp*(dppe)Ru}(µ-C≡CC6 H4 C≡C){Ru(dppe)Cp*}]+ , the low barrier to rotation of the half-sandwich metal fragments and the arylene bridge around the acetylene moieties results in population of many energy minima across the conformational energy landscape. Since orbital overlap is also sensitive to the particular mutual orientations of the metal fragment(s) and arylene bridge through a Karplus-like relationship, the different members of the population range exemplify electronic structures ranging from strongly localized (weakly coupled Robin-Day Class II) to completely delocalized (Robin-Day Class III). Here, we use electronic structure calculations with the hybrid density functional BLYP35-D3 and a continuum solvent model in combination with UV-vis-NIR and IR spectroelectrochemical studies to show that the conformational population in complexes [{Cp*(dppe)Ru}(µ-C≡CArC≡C){Ru(dppe)Cp*]+ , and hence the dominant electronic structure, can be biased through the steric and electronic properties of the diethynylarylene (Ar) moiety (Ar=1,4-C6 H4 , 1,4-C6 F4 , 1,4-C6 H2 -2,5-Me2 , 1,4-C6 H2 -2,5-(CF3 )2 , 1,4-C6 H2 -2,5-i Pr2 ).

Sulfur-Doped Quintuple [9]Helicene with Azacorannulene as Core.

Herein, a hetero(S,N)-quintuple [9]helicene (SNQ9H) molecule with an azacorannulene core was synthesized, currently representing the highest hetero-helicene reported in the field of multiple [n]helicenes. X-ray crystallography indicated that SNQ9H includes not only a propeller-shaped conformer SNQ9H-1, but also an unforeseen quasi-propeller-shaped conformer SNQ9H-2. Different conformers were observed for the first time in multiple [n≥9]helicenes, likely owing to the doping of heteroatomic sulfurs in the helical skeletons. Remarkably, the ratio of SNQ9H-1 to SNQ9H-2 can be regulated in situ by the reaction temperature. Experimental studies on the photophysical and redox properties of SNQ9H and theoretical calculations clearly demonstrated that the electronic structures of SNQ9H depend on their molecular conformations. The strategy of introducing heteroatomic sulfurs into the helical skeleton may be useful in constructing various conformers of higher multiple [n]helicenes in the future.

Binaphthyl-Bridged Pyrenophanes: Intense Circularly Polarized Luminescence Based on a D2 Symmetry Strategy.

A series of D2 -symmetric macrocycles composed of alternately linked pyrene and binaphthyl moieties (binaphthyl-bridged pyrenophanes) have been synthesized. Among them, a pyrenophane possessing ether linkers at the 2,7-positions of the pyrenes exhibited intense circularly polarized luminescence (CPL) with a |glum | value of 0.053. This value is by far the highest for excimers and was not sensitive to temperature, solvent, or concentration. The CPL originated from a twisting pyrene excimer, with the (R)-binaphthyl moieties producing a left-handed twist excimer, which exhibited (-)-CPL. The electric and magnetic transition dipole moments are perfectly parallel, which is the best relationship for strong CPL.

Characterization of Asx Turn Types and Their Connate Relationship with ß-Turns.

Models of asparagine-containing dipeptides specifically designed to favor intrinsic folding into an Asx turn were characterized both theoretically, by using quantum chemistry, and experimentally, by using laser spectroscopy in the gas phase. Both approaches provided evidence for the spontaneous folding of both the Asn-Ala and Asn-Gly dipeptide models into the most stable Asx turn, a conformation stabilized by a C10 H-bond that was very similar to a type II' ß-turn. In parallel, analysis of Asx turns implicating asparagine in crystallized protein structures in the Protein Data Bank revealed a sequence-dependent behavior. In Asn-Ala sequences, the Asx turn was found in conjunction with a type I ß-turn for which the first of the four defining residues was Asn. The observation that the Asx turn in these structures is mostly of type II' (i. e., its most stable innate structure) suggests that this motif might foster the formation and/or enhance the stability of the backbone ß-turn. In contrast, the Asx turns observed in Asn-Gly sequences extensively adopted a type II Asx-turn structure, thus suggesting that their formation should be ascribed to other factors, such as hydration. The fact that the Asx turn in a Asn-Gly sequence is also often found in combination with a hydrated ß-bulge supports the premise that a Asn-Gly sequence might efficiently promote the formation of the ß-bulge secondary structure.

Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices.

The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.

α-Amino-iso-Butyric Acid Foldamers Terminated with Rhodium(I) N-Heterocyclic Carbene Catalysts.

To investigate how remotely induced changes in ligand folding might affect catalysis by organometallic complexes, dynamic α-amino-iso-butyric acid (Aib) peptide foldamers bearing rhodium(I) N-heterocyclic carbene (NHC) complexes have been synthesized and studied. X-ray crystallography of a foldamer with an N-terminal azide and a C-terminal Rh(NHC)(Cl)(diene) complex showed a racemate with a chiral axis in the Rh(NHC) complex and a distorted 310 helical body. Replacing the azide with either one or two chiral L-α-methylvaline (L-αMeVal) residues gave diastereoisomeric foldamers that each possessed point, helical and axial chirality. NMR spectroscopy revealed an unequal ratio of diastereoisomers for some foldamers, indicating that the chiral conformational preference of the N-terminal residue(s) was relayed down the 1 nm helical body to the axially chiral Rh(NHC) complex. Although the remote chiral residue(s) did not affect the stereoselectivity of hydrosilylation reactions catalysed by these foldamers, these studies suggest a potential pathway towards remote conformational control of organometallic catalysts.

Synthesis, Structure, and Dynamics of Chiral Eight-Membered Cyclic Molecules with Thienylene and Cyclopropylene Units Alternately Connected.

A rhodium(II)-catalyzed asymmetric cyclooligomerization of bifunctional monomers possessing triazolyl and vinyl groups at 2,3- and 3,4-positions on the thiophene ring is studied. Structurally interesting cyclic dimers in which thienylene and cyclopropylene units are alternately connected are obtained as the major components. The eight-membered rings in the center are non-planar and adopt a tub-shaped conformation. We also observe the phenomenon of racemization caused by a tub-to-tub ring-flipping, the activation energy of which is determined as 108 kJ mol-1 by electronic circular dichroism spectra measurement.

Ruthenium Complexes Bearing Axially Chiral Bipyridyls: The Mismatched Diastereomer Showed Red Circularly Polarized Phosphorescence.

RutheniumII complexes bearing three axially chiral bipyridyl ligands were synthesized as a new family of chiral complex dyes, and Δ-(S)- and Λ-(S)-diastereomers were obtained. The X-ray crystal structure analyses, spectroscopy, and DFT calculations suggested that all the bipyridyls maintained chirality in both the ground and excited states, and the Δ-(S)- and Λ-(S)-isomers are the matched (more relaxed) and mismatched (more constrained) pairs, respectively. The mismatched Λ-(S)-isomer exhibited red circularly polarized phosphorescence (CPP) both in solution and in the solid state. The solution state CPP is the most intense of ruthenium complexes, while the solid state CPP is the first example of them. It is supposed that, for the Λ-(S)-isomer, the six cumulative CH/π interactions suppress further distortion in the T1 state.

Synthesis, Structures, and Properties of Helically Fused Anthraquinones with Unusually Close Carbonyl-Carbonyl Contacts.

Electron-deficient aromatic ketones consisting of three fused anthraquinone units were synthesized by oxidation of the corresponding fused anthracenes. X-ray analysis revealed that these compounds had nonplanar helical structures with unusual contacts, C=O⋅⋅⋅C=O 2.467 Å, between the inner carbonyl groups. The role of n⋅⋅⋅π* interactions in the short contacts was evaluated using a noncovalent interaction plot and natural bond orbital analysis. The dynamic process involving helical inversion was observed by the variable temperature 1 H NMR measurement of a derivative with 2,4,6-trimethylphenyl groups, and the barrier was estimated to be 77 kJ mol-1 . DFT calculations indicated that the helical inversion proceeded via a multistep mechanism. The characteristic spectroscopic and electrochemical data due to the electron-deficient anthraquinone units and the sterically congested carbonyl groups are discussed with the aid of DFT calculations.

Exhaustive Conformational Search for Sialyl Cation Reveals Possibility of Remote Participation of Acyl Groups.

Finding convenient ways for the stereoselective α-sialylation is important due to the high practical significance of α-sialic acid-containing glycans and neoglycoconjugates. It was proposed that sialylation stereoselectivity is determined by the structure of the sialyl cation (also known in biochemistry as "sialosyl cation"), a supposed intermediate in this reaction. Here we design a new approach for studying the conformational space of highly flexible sialyl cation and find 1625 unique conformers including those stabilized by covalent remote participation (also known as long-range participation) of 4-O-acetyl (4-OAc), 5-N-trifluoroacetyl (5-NTFA), as well as 7,8,9-OAc from both α and ß sides. The most energetically stable sialyl cation conformers are featured by 4-OAc participation, closely followed by 5-NTFA- and 7-OAc-stabilized conformers; unstabilized sialyl cation conformers are ∼10 kcal mol-1 less stable than the 4-OAc-stabilized ones. Analysis of all the obtained conformers by means of substituents positions, side chain conformations and ring puckering led us to a new "eight-conformer hypothesis" which describes interconversions among the most important sialyl cation conformers and predicts that stronger remote participation of acyl groups favors ß-anomers. Thus, selective synthesis of the desired α-sialosides requires minimization of acyl groups participation.