Conformational Behavior Research Articles

Probing ligand-induced conformational changes in an MFS transporter in vivo using site-directed PEGylation.

So far, site-directed alkylation (SDA) studies on transporters in the Major Facilitator Superfamily (MFS) are mostly performed at conditions different from the native cellular environment. In this study, using GFP-based site-directed PEGylation, ligand-induced conformational changes in the lactose permease of Escherichia coli (LacY), were examined in vivo for the first time. Accessibility/reactivity of single-Cys replacements in a Cys-less LacY-eGFP fusion background was tested using methoxy polyethylene glycol-maleimide-5K (mPEG-Mal-5K) in the absence or presence of a ligand, and the band-shift of the fusion upon PEGylation was detected by in-gel fluorescence. Ligand binding increases the rate of PEGylation at five out of eight tested positions on the periplasmic side in vivo, while decreasing the rate of PEGylation at both positions tested on the cytoplasmic side in situ. Upon ligand binding, the rate of PEGylation at two periplasmic positions, K42 and Q242, slightly decreases in vivo, but increases in situ, indicating the conformational behavior of these two residues in living cells may not be identical to that in isolated cell membranes. Furthermore, abolishing the electrochemical H+ gradient (Δµ̃H+) reduces the rate of PEGylation at all tested positions on the periplasmic side. We also found that, unlike the linear form, the branched (Y-shape) mPEG-Mal-5K cannot pass the outer membrane. This work characterizes the alternating access of LacY in the context of a living cell and demonstrates that this methodology is feasible and effective for dynamical studies of MFS transporters.

Albumin Folding Changes Affect the Microfluidic Interfacial Broadening Revealed by Surface Plasmon Resonance

AbstractUnderstanding the conformation and diffusion behavior of proteins in biological fluids is crucial for advancements in conformational disease research. While several experimental techniques are available for probing protein conformations, they often come with limitations, such as the need for fluorophores or specific experimental conditions. Albumin, one of the most abundant proteins in the blood and used as a tear supplement in treating ocular surface disorders, plays a vital role as a transport protein, binding various ligands and facilitating their transport. However, the direct relationship between albumin conformation and diffusion coefficient (D) in water solutions remains unexplored. In this study, we describe a novel Surface Plasmon Resonance technique coupled with Stochastic Gillespie′s algorithm simulations to correlate albumin D values with its conformational states directly. Our findings demonstrate the feasibility of monitoring albumin conformational changes under different environmental conditions, as well as its degradation kinetics by trypsin, by analyzing its diffusion characteristics, presenting a promising avenue for advancing our understanding of conformational diseases.

A Structural Effect of the Antioxidant Curcuminoids on the Aβ(1–42) Amyloid Peptide

Investigating amyloid–β (Aβ) peptides in solution is essential during the initial stages of developing lead compounds that can influence Aβ fibrillation while the peptide is still in a soluble state. The tendency of the Aβ(1–42) peptide to misfold in solution, correlated to the aetiology of Alzheimer’s disease (AD), is one of the main hindrances to characterising its aggregation kinetics in a cell-mimetic environment. Moreover, the Aβ(1–42) aggregation triggers the unfolded protein response (UPR) in the endoplasmic reticulum (ER), leading to cellular dysfunction and multiple cell death modalities, exacerbated by reactive oxygen species (ROS), which damage cellular components and trigger inflammation. Antioxidants like curcumin, a derivative of Curcuma longa, help mitigate ER stress by scavenging ROS and enhancing antioxidant enzymes. Furthermore, evidence in the literature highlights the effect of curcumin on the secondary structure of Aβ(1–42). This explorative study investigates the Aβ(1–42) peptide conformational behaviour in the presence of curcumin and six derivatives using circular dichroism (CD) to explore their interactions with lipid bilayers, potentially preventing aggregate formation. The results suggest that the synthetic tetrahydrocurcumin (THC) derivative interacts with the amyloid peptide in all the systems presented, while cyclocurcumin (CYC) and bisdemethoxycurcumin (BMDC) only interact when the peptide is in a less stable conformation. Molecular dynamics simulations helped visualise the curcuminoids’ effect in an aqueous system and hypothesise the importance of the peptide surface exposition to the solvent, differently modulated by the curcumin derivatives.

Graph-based analysis of H-bond networks and unsupervised learning reveal conformational coupling in prion peptide segments.

In this study, we employed a comprehensive computational approach to investigate the physical chemistry of the water networks surrounding hydrated peptide segments, as derived from molecular dynamics simulations. Our analysis uncovers a complex interplay of direct and water-mediated hydrogen bonds that intricately weave through the peptides. We demonstrate that these hydrogen bond networks encode critical information about the peptides' conformational behavior, with the dimensionality of these networks showing sensitivity to the peptides' conformations. Additionally, we estimated the free-energy landscape of the peptides across various conformations, revealing that their structures are predominantly characterized by unfolded, partially folded, and folded configurations, resulting in broad and rugged free-energy surfaces due to the numerous degrees of freedom contributed by the surrounding solvent. Importantly, the structured nature of this free-energy landscape becomes obscured when conventional collective variables, such as the number of hydrogen bonds, are used. Our findings provide new insights into the molecular mechanisms that couple protein and solvent degrees of freedom, highlighting their significance in the functioning of biological systems.

Effects of Silicon Concentration and Synthesis Duration on Lignin Structure: A Spectroscopic and Microscopic Study.

Silicon (Si) is a highly abundant mineral in Earth's crust. It plays a vital role in plant growth, providing mechanical support, enhancing grain yield, facilitating mineral nutrition, and aiding stress response mechanisms. The intricate relationship between silicification and lignin chemistry significantly impacts cell wall structure. Yet, the precise influence of Si on lignin synthesis remains elusive. This study investigated the interaction between Si and lignin model compounds during invitro synthesis. Employing spectroscopic and microscopic analyses, we delineated how Si concentrations modulate lignin polymerization dynamics, particularly affecting molecular conformation and aggregation behavior over time. Fluctuations in the polymer structure are directly related to both the synthesis time and the concentration of silica. Our results demonstrate that lower Si concentrations promote the aggregation of lignin oligomers into larger particles, while higher concentrations increase the possibility of oligomer repulsion, thus preventing particle growth. These findings elucidate the intricate interplay between Si and lignin, which is crucial for understanding plant cell wall structure and stress resilience. Moreover, the results provide insights for developing lignin-silica materials with increasing applications in industry and medicine.

Investigation of Host-Guest Interactions in 2-Ureido-4-ferrocenylpyrimidine Derivatives.

In the present study, synthesis, conformational behavior, host-guest complex formation, and electrochemical properties of novel 6-substituted-2-ureido-4-ferrocenylpyrimidines were explored. A comprehensive NMR spectroscopic investigation was carried out to confirm the structure and conformational equilibrium of the ureidopyrimidines through studying the temperature- and concentration dependence of NMR spectra. Low-temperature NMR measurements were used to clarify structural changes inflicted by a 2,6-diaminopyridine guest. Association constant (Kassoc) values of host-guest complexes were calculated based on low-temperature titrations. It was shown that the introduction of a pyridin-2-yl substituent in the pyrimidine ring in host 10 induced a considerable change not only in the conformational equilibrium of the host itself but also in that of the host-guest complex. Geometries and relative stabilities of the conformers of host 10 as well as its host-guest complexes were determined by quantum chemical calculations. Electrochemical behavior of ureidopyrimidine hosts and host-guest complexes was investigated by cyclic voltammetry (CV) and linear sweep voltammetry (LSV) measurements. Two ureidopyrimidine derivatives were immobilized on the surface of spectral graphite electrodes, and their electrochemical response on the addition of 2,6-diaminopyridine was compared. These results also supported the importance of the pyridin-2-yl substituent in the efficient sensing of the guest.

Socio-legal anomie: the anthropological dimension

The article is devoted to the philosophical and legal analysis of social and legal anomie based on an anthropological approach, given that the loss of value, legal, and moral guidelines for a person during social anomie, first of all, puts him before the choice of a way of existence through self­realization in a legitimate, or misconduct. It is emphasized that socio-legal anomie, as a crisis-transitional state of the development of society, is inherent in a certain period to all socio-legal formations. In order for society to restore full-fledged civilizational development, it is necessary to form value guidelines based on the norms of natural law according to the principle of anthropocentrism, which provides for the supremacy of the rights and freedoms of man and citizen and their protection by all legal methods and means. It has been found that with socio-legal anomie, the person comes to the fore, namely the need to observe and preserve their rights, freedoms, and human dignity, that is, the principle of human- centeredness is activated. A person with formed legitimate beliefs implements them in his own behavior, and also tries to direct the behavior of others in a legitimate direction, which allows him to avoid deviant behavior. The presence of stable value beliefs and orientations also prevents the manifestation of conformist behavior, in particular among young people. It is noted that today society is used to being guided by legal norms established and sanctioned by the state, and even a slight destabilization of this sphere can cause a certain collapse not only in the sphere of social and legal relations, but also in the personal self-realization of a person. This happens because a person ceases to feel fully protected by the state-legal mechanism and can disregard the principles of social coexistence for the purpose of self-realization. Such a situation often leads to manifestations of deviant behavior, or illegal and criminal behavior. We focus on the fact that natural and legal norms, as an ideal regulator of social relations, become a criterion for determining the lawful behavior of a person. Of course, such norms have always been taken as a basis for the formation of the legal framework in democratic, legal states, because if positive law did not contain the norms of natural law, then it would be purely an instruction of behavior, and not a living and effective law.

Cooperation resonance based on link strategy reinforcement learning and conformity

We propose a game model that integrates reinforcement learning (RL) with link strategies and conformity behavior to investigate the emergence and maintenance of cooperation. The model operates on a lattice network with periodic boundaries and includes two types of nodes: RL nodes with link strategies and conformist nodes. Simulation results reveal a range of critical mass. Within this range, the interaction between these two types of nodes exhibits a nonlinear response between the cooperation rate and the temptation to betray, resulting in the phenomena of resonance-like cooperation and resonance-like defection, showing a nonlinear response between the cooperation rate and the temptation to betray. This study reveals the complex interactions between the two strategies as well as their influence on system behavior through numerical simulations and analysis. Our results provide fresh insights into understanding and promoting cooperative behavior between artificial intelligence and humans.

Mitigating the Effects of Starch Derivatives on Cold Denaturation of Gluten Protein: Insights from Hydration Capacity and Conformation Behavior.

Mitigating the cold denaturation of gluten protein during frozen storage is crucial for the quality improvement of frozen cereal products. Our previous study observed that starch derivatives, especially short-clustered maltodextrin (SCMD), could significantly improve frozen dough quality, alleviating the deterioration of gluten-network structure. To further reveal the cryoprotection mechanism of SCMD on gluten protein during frozen storage, the modulatory roles of SCMD in the hydration capacity and conformation behavior of gluten protein were explored, in comparison with DE2 maltodextrin (MD) and pregelatinized starch (PGS). Results demonstrated that SCMD significantly facilitated the reservation of bound water and decreased the surface hydrophobicity of gluten protein after 8 weeks of frozen storage. Remarkable effects of SCMD on stabilizing the secondary structure and microenvironment of aromatic amino acids of gluten protein were observed. Further mechanistic investigation showed that when the temperature dropped from 300 to 250 K, the short-clustered structure could stabilize the α-helixes more evidently than linear structures through hydrogen bonds with water and steric hindrance effect, rather than directly with protein. Our findings will provide novel insights into the cold denaturation of gluten protein and useful guidance in selecting the optimum structure to suppress this denaturation, improving the quality of frozen cereal products.

MDRepo-an open data warehouse for community-contributed molecular dynamics simulations of proteins.

Molecular Dynamics (MD) simulation of biomolecules provides important insights into conformational changes and dynamic behavior, revealing critical information about folding and interactions with other molecules. The collection of simulations stored in computers across the world holds immense potential to serve as training data for future Machine Learning models that will transform the prediction of structure, dynamics, drug interactions, and more. Ideally, there should exist an open access repository that enables scientists to submit and store their MD simulations of proteins and protein-drug interactions, and to find, retrieve, analyze, and visualize simulations produced by others. However, despite the ubiquity of MD simulation in structural biology, no such repository exists; as a result, simulations are instead stored in scattered locations without uniform metadata or access protocols. Here, we introduce MDRepo, a robust infrastructure that provides a relatively simple process for standardized community contribution of simulations, activates common downstream analyses on stored data, and enables search, retrieval, and visualization of contributed data. MDRepo is built on top of the open-source CyVerse research cyber-infrastructure, and is capable of storing petabytes of simulations, while providing high bandwidth upload and download capabilities and laying a foundation for cloud-based access to its stored data.

Synthesis and characterization of polyimides with rigid folded fragments

The macromolecular chain of conventional polyimide (PI) is a predominant linear extension, which is anticipated to uphold robust interchain interactions essential for preserving overall mechanical and thermal performance. This study is dedicated to the design and synthesis for the novel PIs containing folded chains, with a particular emphasis on modifying the chain conformational behavior with respect to the structure of the aggregation state and the corresponding gas separation properties. First, two unidirectional diamine monomers, dibenzo [c, g] phenanthrene-9,12-diamine (NPDA) and anthracene-1,8-diamine (ADA), were meticulously synthesized through a sequence of chemical reactions, including Witting olefination and photocyclization. These monomers possess distinctive spatial characteristics: NPDA adopts a helical conformation, while ADA maintains a planar structure. Subsequently, the corresponding folded chain-containing PIs, denoted as NPI and API, were successfully achieved by copolymerizing one of the unidirectional monomers with the 6FDA-TPDA system. API and NPI generally exhibit a propensity for enhanced molecular chain stacking, while retaining their good solubility and processability. Drawing from both experimental data and simulation results, it was ascertained that the inclusion of these two monomers produces a rearrangement of pore sizes with a decrease in large-size micropores and an increase in the percentage of ultra-micropores. Moreover, the PI membranes with the folded fragments have a much better CO2 plasticization resistance.

Conformational Changes and Coordination Stability of Flexible Tripeptides During Ni(II)-mediated Self-assembly.

The rational design of artificial supramolecular structures with specific properties and functions hinges the comprehensive understanding of the coordination and noncovalent interactions driving self-assembly. Herein, the self-assembly of supramolecular systems through octahedral coordination between Ni(II) ions and a flexible tripeptide was theoretically investigated using quantum chemical calculations. These calculations utilized the B3LYP functional with the polarizable continuum model. Our results indicate that tridentate sites have a greater propensity for coordination, and that the presence of chloride anions and conformational shifts enhance bidentate and monodentate coordination. Insights into the effect of counter anions on the stability of octahedral coordination and the prerequisites for self-assembly were gained by determining the stable conformation and potential reaction pathways of the tripeptide before and after adding chloride anions through an efficient automated conformational search. The formation of intramolecular hydrogen bonding interactions during the conformational changes was also studied using model calculations. Possible processes for initial self-assembly of tripeptide were proposed. This study enhances the fundamental understanding of the conformational behavior of building blocks during supramolecular formation and advance the potential for constructing future bioinspired complexes.

Impact of water models on the structure and dynamics of enzyme tunnels

Protein hydration plays a vital role in many biological functions, and molecular dynamics simulations are frequently used to study it. However, the accuracy of these simulations is often sensitive to the water model used, a phenomenon particularly evident in intrinsically disordered proteins. Here, we investigated the extent to which the choice of water model alters the behavior of complex networks of tunnels within proteins. Tunnels are essential because they allow the exchange of substrates and products between buried enzyme active sites and the bulk solvent, directly affecting enzyme efficiency and selectivity, making the study of tunnels crucial for a holistic understanding of enzyme function at the molecular level. By performing simulations of haloalkane dehalogenase LinB and its two variants with engineered tunnels using TIP3P and OPC models, we investigated their effects on the overall tunnel topology. We also analyzed the properties of the primary tunnels, including their conformation, bottleneck dimensions, sampling efficiency, and the duration of tunnel openings. Our data demonstrate that all three proteins exhibited similar conformational behavior in both models but differed in the geometrical characteristics of their auxiliary tunnels, consistent with experimental observations. Interestingly, the results indicate that the stability of the open tunnels might be sensitive to the water model used. Because TIP3P can provide comparable data on the overall tunnel network, it is a valid choice when computational resources are limited or compatibility issues impede the use of OPC. However, OPC seems preferable for calculations requiring an accurate description of transport kinetics.

Structural and Functional Relevance of Charge Based Transient Interactions inside Intrinsically Disordered Proteins.

Intrinsically disordered proteins (IDPs) perform a wide range of biological functions without adopting stable, well-defined, three-dimensional structures. Instead, IDPs exist as dynamic ensembles of flexible conformations, traditionally thought to be governed by weak, nonspecific interactions, which are well described by homopolymer theory. However, recent research highlights the presence of transient, specific interactions in several IDPs, suggesting that factors beyond overall size influence their conformational behavior. In this study, we investigate how the spatial arrangement of charged amino acids within IDP sequences shapes the prevalence of transient, specific interactions. Through a series of model peptides, we establish a quantitative empirical relationship between the fraction of transient interactions and a novel sequence metric, termed effective charged patch length, which characterizes the ability of charged patches to drive these interactions. By examining IDP ensembles with varying levels of transient interactions, we further explore their heteropolymeric structural behavior in phase-separated condensates, where we observe the formation of a condensate-spanning network structure. Additionally, we perform a proteome-wide scan for charge-based transient interactions within disordered regions of the human proteome, revealing that approximately 10% of these regions exhibit such charge-driven transient interactions, leading to heteropolymeric behaviors in their conformational ensembles. Finally, we examine how these charge-based transient interactions correlate with molecular functions, identifying specific biological roles in which these interactions are enriched.

Is Conformist Behavior Related to Boreout?

Background. The main reason for conducting such a study is to find the answer to the question of whether the boredom they experience at work is behind these behaviors in business life, where individuals push themselves into the background rather than using their right to speak. In this context, understanding the concept of conformism, which is new in the literature, and analyzing its relationships with relevant variables will contribute to the literature. Aim. The aim of this study is to investigate whether conformist behaviors that individuals frequently encounter and are exposed to in business life are related to boreout experienced for some reasons. Method. In this context, through a relational model designed according to the quantitative research method, the research data obtained from the teachers' sample (n = 325) were subjected to statistical analyses and the findings were reported. Findings. The independent variable boreout and its all-sub-dimensions have a significant and positive contribution to explaining conformist behaviors. 60% of the variance in conformist behaviors can be explained by boredom/boreout at work. Individuals exhibit more conformist behavior by questioning their work, development and meaning due to the boredom they experience. Conclusion. The increase in boreout level of employees, which arises for some reasons in the work environment, will be effective in employees' ability to express their opinions, express their thoughts, and decrease their participation in decisions, in other words, to increase their conformist behaviors. Because individuals want to be comfortable in the work environment where they spend most of their days and not to encounter factors that will cause boredom in order to be able to express themselves and put forward an idea on a subject.

Conformational Selection of Polymer Chains upon π-π Interactions with Small Molecules.

Conformational selection, pivotal in biological molecular recognition, remains underexplored in synthetic polymers, especially in the bulk states of polymers. This study reveals distinct conformational selection behavior in atactic polystyrene melts interacting with polycyclic aromatic hydrocarbons for the first time. Remarkably, despite structural similarities, anthracene and pyrene induce distinctly different conformations-trans and gauche, respectively. This divergence, attributed to the unique π-π interaction geometries, is captured by a "polymer cage" model, providing new insights into the precise structuring of polymers at the secondary structure level.

Impregnation, dehydration and crosslinking of responsive organoboron polymer to generate smart gating membrane for multimolecular gradient separation

Responsive materials have garnered increasing attention in the membrane separation field. However, fabricating smart gating membranes with tunable pore sizes to separate complex systems remains challenging. Herein, gating membranes with boroxine skeleton and temperature-tunable pores were successfully fabricated by fixing lower critical solution temperature (LCST)-type organoboron polymers (poly(N-isopropylacrylamide-co-glycidyl methacrylate/3-aminophenylboronic acid), PNG-APBA) onto the membrane surface via "impregnation-dehydration-crosslinking" strategy. The conformational behavior of the NIPAM-containing polymer chains (shrinking above LCST-stretching below LCST) serves as a functional gate, enabling the membranes to achieve reversibly tunable pore sizes and surface properties. The modified membranes exhibit gradient separation capabilities for small/medium/large molecules in complex polymer systems through temperature-tunable channels. The tunable pores also provided a potential tool for the high-selectivity separation of mixed proteins, such as lysozyme (LZM) and hemoglobin (Hb). Notably, the conformational behavior of the polymer chains endowed the membranes with excellent self-cleaning ability (FRR> 99.5 %), while the boroxine network enhanced the grafting stability of the polymer chains, ensuring effective reversibility and repeatability of membranes.

Silk Fibroin-Based Lenvatinib Nanomedicine with Conformation Tunability for Systemic Treatment of Hepatocellular Carcinoma.

Multitarget tyrosine kinase inhibitors (TKIs) serve as first-line therapeutics in the systemic treatment of hepatocellular carcinoma (HCC), yet their clinical effectiveness is hampered by suboptimal pharmacokinetics and bioavailability. There is a critical need to enhance the circulation, tumor targeting, and infiltration of TKIs. In this context, we developed a silk fibroin (SF)-based nanomedicine that exploits the chemical versatility and conformation tunability of SF. Folic acid (FA) with affinity toward HCC cells is utilized to functionalize SF, simultaneously aiding in the pH-sensitive β-sheet transitions of SF. This dynamic conformation behavior is key to improving the nanomedicine's circulation, biological adhesion, and tumor localization. By encapsulating Lenvatinib (Leva) TKI, the nanomedicine exhibits tumor-targeted accumulation and potent inhibition on HCC cell survival and angiogenesis, thereby amplifying Leva's bioavailability and therapeutic impact. Owing to SF's low immunogenicity and high reproducibility, this SF-based approach for TKI delivery holds substantial promise for advancing HCC systemic therapy.

Evolutionary Perspective on Tourists’ Conformity to the Minority: The Effect of Mating Motive

Tourists tend to conform to the majority when faced with uncertainty in decision-making, which poses a considerable challenge to the promotion of new, less popular tourism offerings. This study delves into the heuristic promotion of less popular tourism offerings by using the concept of mating motives from the field of evolutionary psychology. Findings show that tourists driven by mating motives are likely to follow the minority, rather than the majority, when making purchase decisions—particularly in the context of souvenir shopping, destination selection, and gift giving—with uniqueness seeking playing a mediating role. Although purchase risk can increase the tendency of tourists to conform to the majority, it does not mitigate the effect of mating motives. The findings contribute to the promotion of less popular tourism offerings by highlighting tourists’ uniqueness seeking. This study broadens knowledge on tourist conformity behavior from the theoretical perspective of evolutionary psychology.

Twist along Central C-C Bonds in a Series of Fully π-Fused Propellanes.

Without stereogenic carbon centers, organic molecules can be chiral when they have large energy barriers for conformational inversion. In this work, conformational behaviors are investigated for a series of tricyclic propellane skeletons with increasing 6-membered-ring peripheral moieties fused with aromatic rings. According to theoretical calculations, trinaphtho[3.3.3]propellane has three vertical naphthalene rings like triptycene shape without torsion along the central C-C single bond. On the other hand, hexabenzo[4.4.4]propellane shows hexaphenylethane-like ca. 60° twist along the bond with large activation energy of 64 kcal mol-1 for twist inversion because of the high congestion caused by three 6-membered-ring loops. Indeed, the [4.4.4]propellane gives a stable pair of chiroptical enantiomers toward heating at 146 °C. By contrast, a hybrid [4.3.3]propellane exhibits fast interconversion between two twisted conformations even at -80 °C.