Structure Of Complex Research Articles

SurfPro-NN: A 3D point cloud neural network for the scoring of protein–protein docking models based on surfaces features and protein language models

Protein–protein interactions (PPI) play a crucial role in numerous key biological processes, and the structure of protein complexes provides valuable clues for in-depth exploration of molecular-level biological processes. Protein–protein docking technology is widely used to simulate the spatial structure of proteins. However, there are still challenges in selecting candidate decoys that closely resemble the native structure from protein–protein docking simulations. In this study, we introduce a docking evaluation method based on three-dimensional point cloud neural networks named SurfPro-NN, which represents protein structures as point clouds and learns interaction information from protein interfaces by applying a point cloud neural network. With the continuous advancement of deep learning in the field of biology, a series of knowledge-rich pre-trained models have emerged. We incorporate protein surface representation models and language models into our approach, greatly enhancing feature representation capabilities and achieving superior performance in protein docking model scoring tasks. Through comprehensive testing on public datasets, we find that our method outperforms state-of-the-art deep learning approaches in protein–protein docking model scoring. Not only does it significantly improve performance, but it also greatly accelerates training speed. This study demonstrates the potential of our approach in addressing protein interaction assessment problems, providing strong support for future research and applications in the field of biology.

Synthesis, characterization, crystal structure, molecular docking, and biological studies of Cu, Ni and Co metal complexes of pyrazole

Utilizing ligands based on pyrazole synthesized some transition metal complexes. Selected salts such as Co(CH3COO)2·4H2O, Ni(CH3COO)2·4H2O (in the presence of triethylamine), Cu(CH3COO)2·H2O (in the presence of triethylamine) and CuCl2·2H2O reacted with the ligand (E)-1-(amino(1H-pyrazol-1-yl) methylene) guanidinium chloride in methanol as a solvent. Obtained novel metal complexes characterized using different analyses such as infrared spectroscopy, electrospray ionization mass spectrometry, single-crystal X-ray diffraction, and elemental analysis. Additionally, a novel series of complexes (2a-d) were investigated for their ability to inhibit enzymes. They exhibited highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and α-glycosidase (Ki values are in the range of 7.14 ± 1.97 to 29.34 ± 3.18 µM, 9.86 ± 2.46 to 32.47 ± 4.82 µM, and 2.08 ± 0.11 to 4.03 ± 0.30 µM for hCA I, hCA II, and α-glycosidase, respectively). Indeed, insulin and oral antidiabetic medications are the two mainstays of clinical diabetes treatment. To learn more about the potential of pyrazole-based metal complexes of Cu, Ni, and Co and how successfully they can inhibit hCA I, hCA II, and α-Gly enzymes, molecular docking applications were performed.

New Charge-Transfer Complexes of Organochalcogenide Compound Based on Aryl Acetamide Group with Quinones: Synthesis, Characterization, Antioxidant, and Computational Study

This study aims to prepare charge transfer complexes derived from organochalcogenide of arylamide derivatives with different quinones. A new charge-transfer complexes have been developed through a direct reaction between (PhNHCOCH2)2Se, (o-CH3PhNHCOCH2)2Se, and (PhCH2NHCOCH2)2E, where E = S, Se, and Te are electron donors and different quinones are electron acceptors. The quinones used in the reaction were 2,3-dichloro-5,6-dicyanobenzoquinones (DDQ), 7,7’,8,8’-tetracyanoquinodimethane, and tetracyanoethane. The electron donors and electron acceptor mol were 1:1, and the reaction was conducted in acetonitrile. Infrared, 1H and 13C-NMR spectroscopic data characterized all complexes. The complexes’ antioxidant activity was evaluated through α,α-diphenyl-β-picrylhydrazyl at 10–0.312 mg/mL. The results showed that all complexes exhibited promising antioxidant activities. Among them, (PhCH2NHCOCH2)2S·DDQ compound had the least IC50 value of 6.725 mg/mL, indicating a potent scavenging property compared to other compounds. The molecular structures of charge-transfer complexes were investigated using hybrid density functional theory (B3LYP) and basis set 3-21G. We obtained geometrical structures' highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) surfaces and energy gaps through geometric optimization. We also investigated the molecular shapes and contours of the prepared compounds through geometrical optimization and compared the HOMO energy of the CT compounds to investigate donor and acceptor properties.

A benchmark for evaluation of structure-based online tools for antibody-antigen binding affinity

The prediction of binding affinity changes caused by missense mutations can elucidate antigen-antibody interactions. A few accessible structure-based online computational tools have been proposed. However, selecting suitable software for particular research is challenging, especially research on the SARS-CoV-2 spike protein with antibodies. Therefore, benchmarking of the mutation-diverse SARS-CoV-2 datasets is critical. Here, we collected the datasets including 1216 variants about the changes in binding affinity of antigens from 22 complexes for SARS-CoV-2 S proteins and 22 monoclonal antibodies as well as applied them to evaluate the performance of seven binding affinity prediction tools. The tested tools' Pearson correlations between predicted and measured changes in binding affinity were between −0.158 and 0.657, while accuracy in classification tasks on predicting increasing or decreasing affinity ranged from 0.444 to 0.834. These tools performed relatively better on predicting single mutations, especially at epitope sites, whereas poor performance on extremely decreasing affinity. The tested tools were relatively insensitive to the experimental techniques used to obtain structures of complexes. In summary, we constructed a list of datasets and evaluated a range of structure-based online prediction tools that will explicate relevant processes of antigen-antibody interactions and enhance the computational design of therapeutic monoclonal antibodies.

TRANSFORMATION OF PASSENGER TRANSPORT MANAGEMENT STRUCTURE IN RAILWAY TRANSPORT: WORLD EXPERIENCE AND ITS ADAPTATION TO MODERN CONDITIONS IN UKRAINE

Objective. To enhance the competitiveness of railway passenger transportation in Ukraine, it is necessary to explore the experience of structural transformations in passenger enterprises of foreign railways, analyze the current state of the domestic railway passenger transportation management system, and propose an effective organizational structure for the passenger complex of Ukrainian Railways PJSC in modern conditions. Methodology. To achieve the stated objective, methods of analogy, modeling, comparative, and retrospective analysis were applied. Results. The world experience of interaction between organizational units of railway passenger complexes has been considered. An analysis has been conducted, and problems in the interaction of departments in the existing railway passenger transportation management system have been identified. A management structure for the passenger complex of Ukrainian Railways PJSC has been proposed, which will help optimize its operation and contribute to the increased efficiency of railway passenger transportation in Ukraine. Scientific novelty. The stages of transformation of the management structure of the passenger complex after the formation of Ukrainian Railways PJSC have been generalized. The passenger complex is considered as a single system: based on the visualization of the distribution of work with trains of different categories, problems of delineation of responsibility zones between the departments of the passenger complex have been identified. A model of an improved organizational structure for managing the passenger complex of railway transport has been developed in accordance with modern conditions. Practical significance. The proposed measures can be applied by Ukrainian Railways PJSC to improve the organizational structure of the passenger complex in the process of transitioning to a vertically integrated management model.

Peculiarities of urban planning organization of underground research complexes

The relevance of the construction and operation of underground research facilities specializing in the fields of astrophysics, particle physics, geophysics and biology has developed significantly over the past 30 years. Underground research facilities are able to provide the necessary conditions for conducting experimental studies of physical phenomena that go beyond the Standard Model of Physics. Among the publications devoted to the theoretical foundations of the development of underground urbanism, it is worth noting the works of E. Reynolds, R. Sterling, W. Breuer, and G. Haiko. The main aspects of the architectural and planning and volumetric-spatial structure of underground buildings and structures are outlined in the works of H. Admiral, A. Cornaro, J. Besner. The exploitation of underground space in the conditions of sustainable development of modern cities is studied in the works of L. von der Tann and S. Ritter, Fang-Le Peng, Yong-Kang Xiao. Ukrainian scientists have made a significant contribution to the theoretical issues of underground urbanism: S.V. Ryndyuk, M.A. Maksymenko. Prospects for the integrated development of underground space in Ukraine are highlighted in the works of T.O. Nishchyk. Scientific works of G.I. Gayko are devoted to the priority tasks of development of underground urbanism in Ukraine, assessment of risks of underground construction, historical development of underground space in Ukraine. The historical development of underground buildings and structures is also studied in the works of V. Biletskyi, L. Korkushko, A. Pleshkanovska. The overview of the planning structure of modern underground research complexes is presented in the articles by A. Ianni, A. Bettini, E. Coccia. The article presents a number of prerequisites that influence the choice of a site for the design of underground research complexes in Ukraine. Their brief description is presented. Based on a preliminary analysis of the world experience in designing this type of facilities, important criteria that should be used when choosing a design site are identified. A complete set of functional zones of the master plan of the above-ground territory of the underground research complex is defined. A number of basic recommendations have been formulated that should guide the designer in the development of the master plan.

X-ray structural study of membranes based on Na-CMC and CS-Cl for water purification

The level of environmental pollution is increasing year by year. Solving this problem requires the development and application of new effective technologies and materials for wastewater treatment and processing of accumulated waste. One of the alternative directions is membrane technologies, in particular, the development of biodegradable nanocomposite membranes. Anionic polyelectrolyte – Na-carboxymethyl cellulose with molecular weight Mw ~ 90000 and cationic polyelectrolyte – low molecular weight chitosan were used to create these membranes. Polymeric membranes were formed by mixing aqueous solutions of chitosan hydrochloride and Na-carboxymethylcellulose in different ratios. Analysis of X-ray diffractograms of polyelectrolyte complexes showed that with a gradual increase in the content of cationic polyelectrolyte from 5 % to 17 %, the structure of polyelectrolyte complexes changes dramatically. Whereas, the diffractograms of polyelectrolyte complexes with chitosan content from 29 % to 84 % are similar. The effectiveness of the obtained membranes was tested on a barometric device at different pressures. It was established that membranes based on polyelectrolyte complexes with a stoichiometric ratio of anionic and cationic polyelectrolytes turned out to be the most productive. The degree of water purification was checked by indicators of color selectivity. The obtained results allow us to conclude that with an increase in the duration of purification, the selectivity increases

Assessment of the organizational and economic sustainability of the functioning of integrated technological structures

The paper substantiates the possibility of creating organizational and technological systems in innovative production based on integration into the relevant organizational and production structures, which in the end allows to increase the mobility of the transfer of high technologies in wartime, to reduce the time and complexity of the development and production of the latest products. A methodology for assessing the organizational and economic stability and controllability of the functioning of organizational and production structures in the process of their integration is proposed. This approach makes it possible to assess the integration process as being aimed at a specific result, at compliance with the strategy chosen by the industrial enterprise, and to initiate the necessary organizational and management measures. Also, its use in already created integration organizational and production structures will allow to increase their organizational and economic stability and manageability by ten percent, and the risk of the integration process by five percent; the degree of management by the integrated structure of the work of suppliers with an increase in the level of synergy is considered. The problems of creating integrated structures in the defense-industrial complex are summarized. An assessment of synergistic efficiency in relation to suppliers of materials and components for the production structure was carried out. A new perspective on the interpretation of entropy for evaluating the degree of integration of high-tech systems is provided. Of particular relevance and practical importance today is the development of new methods, concepts and theoretical foundations of strategic management of organizational and economic stability of both an innovative and active enterprise or an organizational and technological system, as well as the integration of industrial enterprises structures. In order to achieve a light level, the enterprise must rely not only on the organizational and technological system of the current level, but also on developing in line with the advances in light technologies and on internal arrangements. the functioning of our minds. The strategic structure will be strengthened rather than lacking the resources and strategic skills necessary to achieve competitiveness in the light market. There is a need for scientifically-based integration of neighboring enterprises in order to improve the efficiency of their functions.

High-Resolution Frequency-Domain Spectroscopic and Modeling Studies of Photosystem I (PSI), PSI Mutants and PSI Supercomplexes.

Photosystem I (PSI) is one of the two main pigment-protein complexes where the primary steps of oxygenic photosynthesis take place. This review describes low-temperature frequency-domain experiments (absorption, emission, circular dichroism, resonant and non-resonant hole-burned spectra) and modeling efforts reported for PSI in recent years. In particular, we focus on the spectral hole-burning studies, which are not as common in photosynthesis research as the time-domain spectroscopies. Experimental and modeling data obtained for trimeric cyanobacterial Photosystem I (PSI3), PSI3 mutants, and PSI3-IsiA18 supercomplexes are analyzed to provide a more comprehensive understanding of their excitonic structure and excitation energy transfer (EET) processes. Detailed information on the excitonic structure of photosynthetic complexes is essential to determine the structure-function relationship. We will focus on the so-called "red antenna states" of cyanobacterial PSI, as these states play an important role in photochemical processes and EET pathways. The high-resolution data and modeling studies presented here provide additional information on the energetics of the lowest energy states and their chlorophyll (Chl) compositions, as well as the EET pathways and how they are altered by mutations. We present evidence that the low-energy traps observed in PSI are excitonically coupled states with significant charge-transfer (CT) character. The analysis presented for various optical spectra of PSI3 and PSI3-IsiA18 supercomplexes allowed us to make inferences about EET from the IsiA18 ring to the PSI3 core and demonstrate that the number of entry points varies between sample preparations studied by different groups. In our most recent samples, there most likely are three entry points for EET from the IsiA18 ring per the PSI core monomer, with two of these entry points likely being located next to each other. Therefore, there are nine entry points from the IsiA18 ring to the PSI3 trimer. We anticipate that the data discussed below will stimulate further research in this area, providing even more insight into the structure-based models of these important cyanobacterial photosystems.

Studying the structure, BSA and FS-DNA interaction, fluorescence sensing of anions, cytotoxicity, and catecholase activity of Cu(II) and Zn(II) Schiff base complexes

Synthesis, characterization, X-ray crystallography, and the interaction with BSA/FS-DNA are reported for two new complexes, [{CuII2L(NCS)2}(μ1,3-NCS)]n (1) and [ZnII2L(μ1,1-N3)(N3)2] (2) (where L=[2,6-bis{N-(2-pyridylethThis section comprises references that occur in the reference list but not in the body of the text. Please position each reference in the text or, alternatively, delete it.yl)formidoyl}-4-methylphenol]). Characterization of the complexes was performed using elemental analysis, UV–vis, and FT-IR spectroscopy. X-ray analysis revealed a thiocyanate-bridged 1-D polymeric structure for complex 1 and a homodinuclear monophenoxo- and azido-bridged structure for complex 2. ‌‌Binding affinity and interaction mode with BSA/FS-DNA were investigated for both complexes using absorption and emission spectroscopy, viscosity measurement, circular dichroism, agarose gel electrophoresis, electrochemical study, and docking simulation. The EtBr replacement experiments clarified an effective binding affinity, Kb = 0.53 × 106 M−1 and Kb = 3.5 × 106 M−1 for complex 1 and 2, respectively, and intercalation as the dominant binding mode for both complexes. Furthermore, the cytotoxicity detection test of the complexes against AGS, MCF-7, PC3 cancer, and NIH/3T3 normal cell lines has shown a moderate selective anticancer activity against MCF-7 and AGS in complex 1. Both complexes triggered apoptosis-programmed cell death. Also, complex 2 showed a sensitive and selective turn-off fluorescence behavior (Kb = 1.1 × 1010 M−1) toward CrO42− among various anions with LOD of 5 × 10−7 M. Moreover, the ability of complex 1 to catalyze the oxidation of 3,5-di‑tert‑butyl catechol (3,5-DTBCH2) to its related quinone, was investigated and it showed an acceptable enzymatic activity.

Novel half-sandwich ruthenium(II) nicotinic hydrazone complexes: An efficient class of catalyst for the N-alkylation of amines with benzyl alcohol via transfer hydrogen mechanism and effective antibacterial agents

A new series of half sandwich ruthenium(II) complexes supported by nicotinic acid hydrazone derivatives of general formula [Ru(ɳ6-p-cymene)(Cl)(L)], where L represents N’-benzylidenenicotinohydrazide (HL1), N’-(naphthalen-1-ylmethylene)nicotinohydrazide (HL2) or N’-(pyren-1-ylmethylene)nicotinohydrazide (HL3) were synthesized and fully characterized. The solid-state molecular structures of ligands and complexes were elucidated with single-crystal X-ray diffraction. The ligands HL1 and HL2 possess monoclinic crystal system with P21/c and C2/c space groups respectively, whereas all the three Ru(II) complexes C1–3 are typical three-legged piano-stool geometries with orthorhombic(Aba2) (C1) and triclinic(P-1) (C2–3) systems respectively. The catalytic activities of these ruthenium complexes in the synthesis of N-alkylated amines were explored. Under optimal reaction condition, the complex C3 was found to be the most efficient catalyst for the N-alkylation of primary to secondary amines using benzyl alcohol. A wide range of substrates have been studied that includes anilines bearing electron withdrawing/electron donating group, fused aromatic, heteroaromatic, alicyclic and aliphatic amines with good to excellent yield. In addition, the antibacterial activity of the complexes were tested against different human pathogenic bacteria, among them C2 complex with naphthyl moiety was found to be the most active one against both Gram-positive (S. aureus and E. faecalis) and Gram-negative (E. coli and K. pneumoniae) bacteria. These two different studies demonstrate the catalytic and biological importance of our newly prepared Ruthenium complex.

Population genetic structure of bottlenose and whitespotted wedgefishes from the Southwest Indian Ocean using a dual marker approach

Wedgefishes (Rhinidae) are threatened by unsustainable fishing globally, and especially in the Southwest Indian Ocean (SWIO), due to their high-value fins in the shark trade. The whitespotted wedgefish Rhynchobatus djiddensis and the bottlenose wedgefish R. australiae are both classified as Critically Endangered on the IUCN Red List of Threatened Species, yet a lack of species-specific knowledge and taxonomic uncertainty still exists within this genus. Genetic approaches aid in taxonomic classification and identifying distinct populations for targeted conservation. Morphological specimen identification of samples (n = 189) collected across the SWIO was confirmed based on the cytochrome oxidase c subunit I (COI) and/or nicotinamide adenine dehydrogenase subunit 2 (ND2) gene regions. The genetic diversity and population structure within and between species and sampling locations were investigated using a dual marker approach: (1) 2 concatenated mitochondrial gene regions, namely COI and the control region (n = 117), and (2) 9 nuclear microsatellite markers (n = 146). The overall genetic diversity was moderate, with an indication that different evolutionary forces are at play on a mitochondrial versus nuclear level. The 2 species were delineated based on both marker types, and for R. djiddensis, the sampling locations of South Africa and Mozambique were genetically homogeneous. For R. australiae, significant differentiation was found between sampling locations, with Madagascar and Tanzania being genetically the most similar. This information provides critical insights into the distribution range and population structure of the whitespotted wedgefish species complex that can support the sustainable management of wedgefishes.

Structural basis of exoribonuclease-mediated mRNA transcription termination.

Efficient termination is required for robust gene transcription. Eukaryotic organisms use a conserved exoribonuclease-mediated mechanism to terminate the mRNA transcription by RNA polymerase II (PolII)1-5. Here we report two cryogenic electron microscopy structures of Saccharomyces cerevisiae PolII pre-termination transcription complexes bound to the 5'-to-3' exoribonuclease Rat1 and its partner Rai1. Our structures show that Rat1 displaces the elongation factor Spt5 to dock at the PolII stalk domain. Rat1 shields the RNA exit channel of PolII, guides the nascent RNA towards its active centre and stacks three nucleotides at the 5' terminus of the nascent RNA. The structures further show that Rat1 rotates towards PolII as it shortens RNA. Our results provide the structural mechanism for the Rat1-mediated termination of mRNA transcription by PolII in yeast and the exoribonuclease-mediated termination of mRNA transcription in other eukaryotes.

Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2.

Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named 'L' and 'R,' where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.

Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2

Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named ‘L’ and ‘R,’ where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.

HighFold: accurately predicting structures of cyclic peptides and complexes with head-to-tail and disulfide bridge constraints.

In recent years, cyclic peptides have emerged as a promising therapeutic modality due to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes is crucial for unlocking invaluable insights about protein target-cyclic peptide interaction, which can facilitate the development of novel-related drugs. However, conducting experimental observations is time-consuming and expensive. Computer-aided drug design methods are not practical enough in real-world applications. To tackles this challenge, we introduce HighFold, an AlphaFold-derived model in this study. By integrating specific details about the head-to-tail circle and disulfide bridge structures, the HighFold model can accurately predict the structures of cyclic peptides and their complexes. Our model demonstrates superior predictive performance compared to other existing approaches, representing a significant advancement in structure-activity research. The HighFold model is openly accessible at https://github.com/hongliangduan/HighFold.

Ligand Field Sensitive Spin Acceleration in the Iron-Catalyzed [2 + 2] Cycloaddition of Unactivated Alkenes and Dienes.

Redox-active pyridine(diimine) (PDI) iron catalysts promote the reversible [2 + 2] cycloaddition of alkenes and dienes to cyclobutane derivatives that have applications ranging from fuels to chemically recyclable polymers. Metallacycles were identified as key intermediates, and spin crossover from the singlet to the triplet surface was calculated to facilitate the reductive coupling step responsible for the formation of the four-membered ring. In this work, a series of sterically and electronically differentiated PDI ligands was studied for the [2 + 2] cycloaddition of ethylene and butadiene to vinylcyclobutane. Kinetic studies revealed that the fastest and slowest turnover were observed with equally electron-deficient supporting ligands that either feature phenyl-substituted imine carbon atoms (MeBPDI) or a pyrazine core (MePZDI). While the oxidative cyclization was comparatively slow for both catalysts, the rate of reductive coupling─determined by stoichiometric 13C2H4 labeling studies─correlated with the turnover frequencies. Two-state density functional theory studies and the distinct electronic structures of related (iPrBPDI) and (iPrPZDI) iron methyl complexes revealed significantly different ligand field strengths due to either diminished ligand σ-donation (MeBPDI) or promoted metal π-backbonding (MePZDI). Spin acceleration, leading to fast reductive coupling and catalytic turnover, was promoted in the case of the weaker ligand field and depends on both the nature and position of the electron-withdrawing group. This study provides strong evidence for the role of two-state reactivity in C(sp3)-C(sp3) bond formation and insights on how ligand design either promotes or inhibits spin acceleration in earth-abundant metal catalysis.

The Cyclic Imine Core Common to the Marine Macrocyclic Toxins Is Sufficient to Dictate Nicotinic Acetylcholine Receptor Antagonism.

Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.

HIPPO: HIstogram-based Pseudo-POtential for scoring protein-ssRNA fragment-based docking poses

BackgroundThe RNA-Recognition motif (RRM) is a protein domain that binds single-stranded RNA (ssRNA) and is present in as much as 2% of the human genome. Despite this important role in biology, RRM-ssRNA interactions are very challenging to study on the structural level because of the remarkable flexibility of ssRNA. In the absence of atomic-level experimental data, the only method able to predict the 3D structure of protein-ssRNA complexes with any degree of accuracy is ssRNA’TTRACT, an ssRNA fragment-based docking approach using ATTRACT. However, since ATTRACT parameters are not ssRNA-specific and were determined in 2010, there is substantial opportunity for enhancement.ResultsHere we present HIPPO, a composite RRM-ssRNA scoring potential derived analytically from contact frequencies in near-native versus non-native docking models. HIPPO consists of a consensus of four distinct potentials, each extracted from a distinct reference pool of protein-trinucleotide docking decoys. To score a docking pose with one potential, for each pair of RNA–protein coarse-grained bead types, each contact is awarded or penalised according to the relative frequencies of this contact distance range among the correct and incorrect poses of the reference pool. Validated on a fragment-based docking benchmark of 57 experimentally solved RRM-ssRNA complexes, HIPPO achieved a threefold or higher enrichment for half of the fragments, versus only a quarter with the ATTRACT scoring function. In particular, HIPPO drastically improved the chance of very high enrichment (12-fold or higher), a scenario where the incremental modelling of entire ssRNA chains from fragments becomes viable. However, for the latter result, more research is needed to make it directly practically applicable. Regardless, our approach already improves upon the state of the art in RRM-ssRNA modelling and is in principle extendable to other types of protein-nucleic acid interactions.

Visualizing Noncovalent Interactions and Property Prediction of Submicron-Sized Charge-Transfer Crystals from ab-initio Determined Structures.

The charge-transfer (CT) interactions between organic compounds are reflected in the (opto)electronic properties. Determining and visualizing crystal structures of CT complexes are essential for the design of functional materials with desirable properties. Complexes of pyranine (PYR), methyl viologen (MV), and their derivatives are the most studied water-based CT complexes. Nevertheless, very few crystal structures of CT complexes have been reported so far. In this study, the structures of two PYRs-MVs CT crystals and a map of the noncovalent interactions using 3D electron diffraction (3DED) are reported. Physical properties, e.g., band structure, conductivity, and electronic spectra of the CT complexes and their crystals are investigated and compared with a range of methods, including solid and liquid state spectroscopies and highly accurate quantum chemical calculations based on density functional theory (DFT). The combination of 3DED, spectroscopy, and DFT calculation can provide important insight into the structure-property relationship of crystalline CT materials, especially for submicrometer-sized crystals.