Conformational Features Research Articles

G protein peptidomimetics reveal allosteric effects and stepwise interactions in ghrelin receptor-G protein coupling.

G protein-coupled receptor (GPCR) signaling is a dynamic process involving various conformational intermediates in addition to those captured in static three-dimensional structures. Here, we used newly developed G protein peptidomimetics to characterize the interactions of the ghrelin receptor (GHSR) with G proteins. Coupling to the G protein peptidomimetic not only affected the conformational features of the cytoplasmic regions of the receptor where the G protein binds but also allosterically affected the extracellular ligand-binding pocket. These conformational and allosteric changes increased the affinity of G protein-coupled GHSR for the endogenous agonist ghrelin. In addition, our data identified different complexes along the G protein activation pathway that differed in the engagement of the Gαq C-terminal helix. Given that this helix is the main link between the activated receptor and the Gα nucleotide-binding pocket, these findings suggested a stepwise process involving distinct states in GPCR-catalyzed G protein activation. Collectively, our results provide evidence for the dynamic behavior of GPCR-G protein signaling complexes, with such dynamics most likely contributing to signaling selectivity and/or efficacy.

The influence of γ-aminobutyric acid production and fat content on the gel properties, protein conformation, and nutritional characteristics of fermented milk: Achieved through interactions with milk proteins

The influence of γ-aminobutyric acid production and fat content on the gel properties, protein conformation, and nutritional characteristics of fermented milk: Achieved through interactions with milk proteins

ЭКСТЕРЬЕРНО-КОНСТИТУЦИОНАЛЬНЫЕ ОСОБЕННОСТИ КОРОВ В ЗАВИСИМОСТИ ОТ ВОЗРАСТА И ГЕНОТИПОВ

The purpose of the study is to identify the influence of Holstein breeders on the exterior features of improved red steppe cattle. To study the exterior features of cows, three groups of cows were formed, from which the main body measurements were taken at 2–3 months of the first, second and third lactations, body indexes were calculated according to generally accepted methods. Groups of experimental animals were characterized by different indicators of body measurements, which is due to the genotype and age characteristics. Holsteinized first-calf heifers were distinguished by higher values of height at the withers, which exceeded the cows of the control group by 1.7–3.8 %. Primary heifers of the control group and three-breed crossbreds of the first generation were characterized by similar chest depth values (P < 0.95) and were inferior to three-breed crossbreds of the second generation by 4.1 and 4.6 % (P < 0.95 and P > 0.95), respectively . An analysis of chest width showed that the use of Holstein sires on an array of red steppe cattle had an impact on the development of chest width. With age, there is some change in the proportions of the body of the experimental groups of cows. Compared with the first lactation, the indexes of stretchiness, massiveness, chest, boneiness and broad chest increased in the anglerized cows of the second lactation. During the specified period, the indexes of overgrowth, stretching, massiveness, chest and broad chest increased in Holsteinized cows of the first generation, while in animals of the second generation there was an increase in the indices of stretch, massiveness, chest and broad chest. Anglerized and Holsteinized crossbred animals are generally characterized by a pronounced type of dairy cattle. An assessment of the improved herds of red steppe cattle was carried out according to the conformation and constitutional features, differences were revealed in the exterior of crossbred cows, depending on the proportion of Holstein bloodlines.

Conformational features of HVEM protein upon its cis and trans binding to BTLA protein

Conformational features of HVEM protein upon its cis and trans binding to BTLA protein

SEE: A Method for Predicting the Dynamics of Chromatin Conformation Based on Single-Cell Gene Expression.

The dynamics of chromatin conformation involve continuous and reversible changes within the nucleus of a cell, which participate in regulating processes such as gene expression, DNA replication, and damage repair. Here, SEE is introduced, an artificial intelligence (AI) method that utilizes autoencoder and transformer techniques to analyze chromatin dynamics using single-cell RNA sequencing data and a limited number of single-cell Hi-C maps. SEE is employed to investigate chromatin dynamics across different scales, enabling the detection of (i) rearrangements in topologically associating domains (TADs), and (ii) oscillations in chromatin interactions at gene loci. Additionally, SEE facilitates the interpretation of disease-associated single-nucleotide polymorphisms (SNPs) by leveraging the dynamic features of chromatin conformation. Overall, SEE offers a single-cell, high-resolution approach to analyzing chromatin dynamics in both developmental and disease contexts.

Dynamics of polymers in coarse-grained nematic solvents.

Polymers are a primary building block in many biomaterials, often interacting with anisotropic backgrounds. While previous studies have considered polymer dynamics within nematic solvents, rarely are the effects of anisotropic viscosity and polymer elongation differentiated. Here, we study polymers embedded in nematic liquid crystals with isotropic viscosity via numerical simulations to explicitly investigate the effect of nematicity on macromolecular conformation and how conformation alone can produce anisotropic dynamics. We employ a hybrid multi-particle collision dynamics and molecular dynamics technique that captures nematic orientation, thermal fluctuations and hydrodynamic interactions. The coupling of the polymer segments to the director field of the surrounding nematic elongates the polymer, producing anisotropic diffusion even in nematic solvents with isotropic viscosity. For intermediate coupling, the competition between background anisotropy and macromolecular entropy leads to hairpins - sudden kinks along the backbone of the polymer. Experiments of DNA embedded in a solution of rod-like fd viruses qualitatively support the role of hairpins in establishing characteristic conformational features that govern polymer dynamics. Hairpin diffusion along the backbone exponentially slows as coupling increases. Better understanding two-way coupling between polymers and their surroundings could allow the creation of more biomimetic composite materials.

Triplet Harvesting in Trifluoromethyl Quinoxaline Derivatives via TADF and RTP Mechanisms

In this study, we explore the impact of donor strength on the photophysical properties of novel trifluoromethyl quinoxaline derivatives, which incorporate various electron-donating moieties exhibiting distinct conformational characteristics. The triplet harvesting mechanisms within these quinoxaline systems are facilitated through thermally activated delayed fluorescence (TADF) and room-temperature phosphorescence (RTP), both of which can be modulated by subtle structural alterations in the donor unit. The derivatives demonstrate varying photophysical properties, including pure RTP activity, dual activity (exhibiting both TADF and RTP), and pure TADF, contingent upon the nature of the electron-donating moieties employed. Notably, the intersystem crossing (ISC) rates are significantly higher than the rates of radiative decay, leading to diminished fluorescence quantum yields (ΦDF) of the compounds in toluene solutions. However, embedding the TADF compounds within a rigid polystyrene (PS) matrix results in a remarkable enhancement of ΦDF due to significant reduction of nonradiative pathways related to intramolecular twisting. A considerable conformational disorder of the polymer doped films was observed resulting in non-exponential fluorescence decay and significant shifts of prompt and delayed fluorescence in time-resolved spectra.

Cheminformatics-based design and biomedical applications of a new Hydroxyphenylcalix[4] resorcinarene as anti-cancer agent

The distinct conformational characteristics, functionality, affordability, low toxicity, and usefulness make calixarene-based compounds a promising treatment option for cancer. The aim of the present study is to synthesize a new calixarene-based compound and assess of its anticancer potential on some human cancer cells. The synthesized C-4-Hydroxyphenylcalix[4] resorcinarene (HPCR) was characterized by several spectroscopic techniques such as 1HNMR, 13CNMR, and X-ray crystallographic analysis to confirm its purity and identity. IC50 values were identified for cancer cell lines (U-87, MCF-7, A549) and human dermal fibroblasts cell line (HDF) after treatment with HPCR and the standard drug Cisplatin. A significant selective growth inhibitory activity against U-87 and A549 cell lines was obtained at an HPCR concentration of 100 μM. The MOE docking module (version 2015) was utilized to assess the extent of inhibition for HPCR compound against four cancer-related proteins (3RJ3, 7AXD, 6DUK, and 1CGL).

Targeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms.

Background/Objectives: The mammalian target of the rapamycin (mTOR) signaling pathway is a central regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling contributes to many human diseases, including cancer, diabetes, and obesity. Therefore, inhibitors against mTOR's catalytic kinase domain (KD) have been developed and have shown significant antitumor activities, making it a promising therapeutic target. The ATP-KD interaction is particularly important for mTOR to exert its cellular functions, and such inhibitors have demonstrated efficient attenuation of overall mTOR activity. Methods: In this study, we screened the Traditional Chinese Medicine (TCM) database, which enlists natural products that capture the relationships between drugs targets and diseases. Our aim was to identify potential ATP-competitive agonists that target the mTOR-KD and compete with ATP to bind the mTOR-KD serving as potential potent mTOR inhibitors. Results: We identified two compounds that demonstrated interatomic interactions similar to those of ATP-mTOR. The conformational stability and dynamic features of the mTOR-KD bound to the selected compounds were tested by subjecting each complex to 200 ns molecular dynamic (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA) to extract free binding energies. We show the effectiveness of both compounds in forming stable complexes with the mTOR-KD, which is more effective than the mTOR-KD-ATP complex with more robust binding affinities. Conclusions: This study implies that both compounds could serve as potential therapeutic inhibitors of mTOR, regulating its function and, therefore, mitigating human disease progression.

Vibrational, electronic properties Pharmaceutical study of 4-Carboxy-3-Fluorophenylboronic acid and ability to form its dimer by using Density functional theory

The motive of present article is to attract attention on conformational analysis and electronic features of 4-carboxy-3-fluorophenylboronic acid compound via computational method. To comply this, density functional theory (DFT) in combination with Becke 3-parameter Lee–Yang–Parr (B3LYP) functional was considered to identify possible conformers and hence the ground state conformation. The stability reaction of formation quantum theory of atoms in molecules (QTAIM), natural bond analysis (NBO) and thermodynamical stability of dimerization of 4-carboxy-3-fluorophenylboronic acid is computed by using DFT/6-31G(d, p) method. The Eigen value of highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), and related energy bandgap were computed at B3LYP. In addition to these, thermodynamic properties and nonlinear properties (NLO) are also computed. Study of NLO (nonlinear optical behavior) reveals the nonlinear properties of the title molecule. The UV-Vis spectra of title molecule were calculated by time dependent density functional theory (TDDFT/6-31G(d, p)) on optimized geometry by same level theory. The biological activity of title molecule is computed by PASS online server which predict 4000 types of biological activities, counting pharmacological effects, mechanisms of action, toxic and adverse effects, interaction with metabolic enzymes and transporters, influence on gene expression, etc. The title molecule showed good activity against antineoplastic (0.914), peptidyl transferase inhibitor (0.969), aminoacylase inhibitor (0.960), sugar-phosphatase inhibitor (0.913), ribulose-phosphate 3-epimerase inhibitor (0.896), antiviral (0.862), TP53 expression enhancer (0.860). To determine anti-inflammatory potential, we have performed docking of title molecule with drosophila, which is a muscleblind like splicing regulator 1 (MBNL1) protein, by using Swiss dock online server.

Self-Assembly of Supramolecular Double Helix from a Tetrapeptide and Direct Visualization by Scanning Tunneling Microscopy.

This work reports single-crystal X-ray diffraction (XRD), Scanning Tunneling Microscopy (STM), and quantum mechanics calculations of the 310-helical peptide Z-(Aib)2-L-Dap(Boc)-Aib-NHiPr (Aib, α-aminoisobutyric acid; Dap, 2,3-diaminopropionic acid; Z, benzyloxycarbonyl; Boc, t-butoxycarbonyl). The peptide forms a double-helical superstructure, studied by XRD and STM. Such architecture is rare in short peptides. Here, we show, by combining XRD and STM that this intriguing conformational feature is not driven by crystal packing; rather, it is an intrinsic property of this peptide. Indeed, the double helix is clearly detected also by STM, where crystal packing cannot be invoked. XRD reveals that intermolecular H-bonds stabilize two left-handed supra-helices (tertiary structure) that develop around a 6-fold screw axis. Then, two supra-helices are intertwined in a quaternary structure as a left-handed, double supra-helix, where C-H⋯π interactions play a crucial role. STM images show the formation of long, isolated "necklaces" (>110 nm). They are of left and right helical handedness. Their size agrees with the XRD finding. DFT calculations allowed us to weigh the contribution of the different intermolecular interactions in the two single supra-helices and the supramolecular double-helix. Interestingly, we were able to conclude that the contribution of the C-H⋯π interactions to the binding energies is close to 50 %.

Molecular Propeller Tethering on a Dipeptide Induces a One-Step Conversion of Its Secondary Structure on Water Surface Promoted by Chiral Supramolecular Assembly.

Water provides a unique surface for the formation of directed self-assembly and transformation of secondary structures of peptides and proteins as witnessed in the biological systems. Herein a one-step transformation of an amyloid-derived dipeptide is reported from β-sheet to α-helix structures on the water surface, facilitated by chiral supramolecular assembly. The study utilizes various analytical techniques to elucidate the structural transformation and the supramolecular packing of the peptide assemblies. Organizations such as spherical aggregates and molecular nanowires containing β-sheet structure are converted into (2D) molecular sheets comprising a larger planar area yet with a molecular level thickness of α-helix structure. The conformational features of the β-sheet to α-helix structural transformation are dominated by the intermolecular H-bonding, π-π stacking, and C─H···π interactions. Strikingly, the dynamic changes in the dihedral (intramolecular) angle between the aromatic rings of the dipeptide at the water surface alter the molecular packing and shorten the intermolecular H-bonds with larger binding energies required for the secondary structural transformation. Thus, the novel one-step strategy reports herein offers a simple, efficient, and hitherto unprecedented way of chiral supramolecular assembly directed total secondary structural transformation of the dipeptide on water surface.

Understanding the Directed Evolution of a Natural-like Efficient Artificial Metalloenzyme.

The artificial metalloenzyme containing iridium in place of iron along with four directed evolution mutations C317G, T213G, L69V, and V254L in a natural cytochrome P450 presents an important milestone in merging the extraordinary efficiency of biocatalysts with the versatility of small molecule chemical catalysts in catalyzing a new-to-nature carbene insertion reaction. This is a show-stopper enzyme, as it exhibits a catalytic efficiency similar to that of natural enzymes. Despite this remarkable discovery, there is no mechanistic and structural understanding as to why it displays extraordinary efficiency after the incorporation of the four active site mutations by directed evolution methods, which so far has been intractable to any experimental methods. In this study, we have deciphered how directed evolution mutations gradually alter the protein conformational ensemble to populate a catalytically active conformation to boost a multistep catalysis in a natural-like artificial metalloenzyme using large-scale molecular dynamics simulations, rigorous quantum chemical (QM), and multiscale quantum chemical/molecular mechanics (QM/MM) calculations. It reveals how evolution precisely positions the cofactor-substrate in an unusual but effective orientation within a reshaped active site in the catalytically active conformation stabilized by C-H···π interactions from more ordered mutated L69V and V254L residues to achieve preferential transition state stabilization compared to the ground state. This work essentially tracks down in atomistic detail the shift in the conformational ensemble of the highly active conformation from the less efficient single mutant to the most efficient quadruple mutant and offers valuable insights for designing better enzymes. The active conformation correctly reproduces the experimental barrier height and also accounts for the catalytic effect, which is in good agreement with experimental observations. Moreover, this conformation features an unusual bonding interaction in a metal-carbene species that preferentially stabilizes the rate-determining formation of an iridium porphyrin carbene intermediate to render the observed high catalytic rate acceleration. Our study provides crucial insights into the underlying rationale for directed evolution, reports the major catalytic role of nonelectrostatic interactions in enzyme catalysis different from the electrostatic model, and suggests a crucial principle toward designing enzymes with natural efficiency.

PH-shifting and sonication synergistically altered cottonseed protein: Correlating the conformational and functional characteristics

pH-shifting (pH 1.5, 3.5, 9.5, 11.5) and sonication were exclusively and synergistically used to produce cottonseed meal protein (CSMP) with modified structure and improved functionality. Conventionally extracted CSMP served as control. Combined pH-shifting and sonication considerably reduced the β-sheet (40 – 27 %), but increased random coil (12 – 34 %) and β-turn (25 – 35 %) content of CSMP, suggesting partial unfolding in the secondary structure of the protein. From scanning electron microscopy and UV-VS spectroscopy data, the synergistic use of alkaline pH-shifting and ultrasonication resulted in the production of CSMP that had disintegrated microstructure and smaller particle sizing, with higher peak absorption, compared with the control; indicating the collapse of intramolecular hydrogen bonds and interactive forces among CSMP molecules. Further, pH-shifting and/or ultrasonication remarkably strengthened sulfhydryl clusters and surface hydrophobicity, but decreased the disulfide bonds and lightness of CSMP. Most importantly, combined treatment at alkaline conditions increased absolute surface charge, solubility, foamability, and oil binding efficacy over control, and pH-shifting alone (p < 0.05). Contrarily, CSMP isolates modified with sequential treatment displayed a reduction in foaming stability (supported by foaming morphology) and water holding efficacy. Overall, the findings indicated that synergistic pH-shifting/sonication may help increase the utilization of CSMP in the development of new food ingredients.

The influence of pH-ultrasonic-induced myofibrillar protein conformation of Penaeus vannamei (Litopenaeus vannamei) on emulsification and digestion characteristics of fish oil oleogel-based emulsions

pH-induced and ultrasound treatment can both adjust spatial conformation to improve the interfacial stability, and fish oil oleogel could be used to enhance oil binding capacity. The relationship between stabilization mechanism and lipid digestion was revealed, considering the protein conformation and interfacial characteristics. The results showed that pH-ultrasonic-induced myofibrillar proteins (MPs) at pH 7.0 had higher interfacial adsorption capacity and surface hydrophobicity as well as more stable secondary structures, which lowered the particle size and enhanced the interfacial stability. In the stomach, the particle size increased along with the decrease in electrostatic repulsion, and β-sheets significantly increased, which promoted aggregation and flocculation. In the small intestine, the reduction of β-sheets favored the interfacial replacement and facilitated the lipid digestion. Therefore, pH-ultrasonic-modified method improved the structure and function of MPs, facilitated the interfacial stability and intestinal digestion.

Physics-Based Machine Learning Trains Hamiltonians and Decodes the Sequence-Conformation Relation in the Disordered Proteome.

Intrinsically disordered proteins and regions (IDPs) are involved in vital biological processes. To understand the IDP function, often controlled by conformation, we need to find the link between sequence and conformation. We decode this link by integrating theory, simulation, and machine learning (ML) where sequence-dependent electrostatics is modeled analytically while nonelectrostatic interaction is extracted from simulations for many sequences and subsequently trained using ML. The resulting Hamiltonian, combining physics-based electrostatics and machine-learned nonelectrostatics, accurately predicts sequence-specific global and local measures of conformations beyond the original observable used from the simulation. This is in contrast to traditional ML approaches that train and predict a specific observable, not a Hamiltonian. Our formalism reproduces experimental measurements, predicts multiple conformational features directly from sequence with high throughput that will give insights into IDP design and evolution, and illustrates the broad utility of using physics-based ML to train unknown parts of a Hamiltonian, rather than a specific observable, in combination with known physics.

Smart Bioinspired Material‐Based Actuators: Current Challenges and Prospects

This research review discusses several examples of plant movements, either depending on the direction of the triggering stimuli (tropisms) or not (nastic responses), which have served as inspiration to develop smart biomimetic actuators. In addition, it presents an overview of the multiple approaches for the development of autonomous actuators based on synthetic materials, as well as of their advantages and disadvantages, applicability, and limitations. The classification is based on structural and conformational characteristics (mono‐, bi‐, or multimaterial assemblies, their orientation, chemical structures, and geometrical configurations). Additionally, this review presents an alternative formulation and extension of the pioneering Timoshenko's model, which provides an understanding of the underlying mechanical principle of bilayer bending actuation. Finally, upscaled applications of this actuation principle are described, focusing mainly on biomimetic architecture. Attention is given to previously reported real‐life applications based on bio‐based materials and material systems. Furthermore, this review discusses the multiple challenges for synthetic materials when an upscaling perspective is intended. In this sense, key aspects such as time responsiveness and mechanical amplification, in terms of speed, displacement, and load‐bearing capability, are discussed.

A Comparative In Vitro Anticancer Evaluation and In Silico Study of New 1‐(1,3‐Oxazol‐5‐yl)piperidine‐4‐sulfonylamides

AbstractIn this work, we synthesized a series of new 1,3‐oxazole derivatives comprising the sulfonylamide group and tested their activity against the human tumor cell line panel. This study further explores the stereoelectronic characteristics of 1,3‐oxazol‐5‐sulfonylamides and new 1‐(1,3‐oxazol‐5‐yl)piperidine‐4‐sulfonylamides to connect their anticancer activity to the molecular structure. Combining in vitro and in silico methods, we analyzed how the proximity of the sulfonylamide group to the heterocyclic ring affects the structure–activity interplay. Herein, our assessment is based on the purported complexation of 1,3‐oxazoles with targeted biomolecular fragments involving the π‐stacking interaction and hydrogen bonding within the prospective complexes. Defining the probability of the prospective drug–target interactions, we detail conformational properties, donor/acceptor capabilities, electronic characteristics, and thermodynamic preference of produced sulfanylamide group containing 1,3‐oxazoles toward biomolecular fragments, identifying the nature of variations in anticancer activity.

Mechanisms of action of fungal polysaccharides and their therapeutic effect.

The purpose of this article is to discuss the relationship between the therapeutic bioactivity of basidial fungal polysaccharides (BFPs) BFPs and their structural characteristics and conformational features, as well as to characterize the mechanisms of action of BFPs in diseases of various origins. The review was conducted using the PubMed (Medline), Scopus, Web of Science and the Russian Science Citation Index databases. 8645 records were identified, of which 5250 were studies (86 were randomized controlled trials). The period covered is from 1960 to the present. The most significant studies conducted mainly in Southeast Asian countries were selected for the review. Based on clinical studies, as well as the results obtained on in vivo, in vitro and ex vivo models, it has been proven that BFPs have diverse and highly effective biological activity in the human body in various diseases. The production of BFPs-based vaccines is an innovative strategy from a clinical and biochemical point of view, since as potential immunoprotective and low-toxic biopolymers they have innate immune receptors in the body. Promising results have been obtained in the development of antidiabetic drugs, probiotic, renoprotective and neurodegenerative dietary supplements. The biological activity, mechanism of action and specific therapeutic effect of BFPs largely depend on their structural and physicochemical characteristics. BFPs as multifunctional macromolecular complexes with low toxicity and high safety are ideal as new powerful pharmaceuticals for the treatment and prevention of many diseases.

SeqDance: A Protein Language Model for Representing Protein Dynamic Properties.

Proteins perform their functions by folding amino acid sequences into dynamic structural ensembles. Despite the important role of protein dynamics, their complexity and the absence of efficient representation methods have limited their integration into studies on protein function and mutation fitness, especially in deep learning applications. To address this, we present SeqDance, a protein language model designed to learn representation of protein dynamic properties directly from sequence alone. SeqDance is pre-trained on dynamic biophysical properties derived from over 30,400 molecular dynamics trajectories and 28,600 normal mode analyses. Our results show that SeqDance effectively captures local dynamic interactions, co-movement patterns, and global conformational features, even for proteins lacking homologs in the pre-training set. Additionally, we showed that SeqDance enhances the prediction of protein fitness landscapes, disorder-to-order transition binding regions, and phase-separating proteins. By learning dynamic properties from sequence, SeqDance complements conventional evolution- and static structure-based methods, offering new insights into protein behavior and function.