Search Results (400)

Elucidating amyloid formation inside biomolecular condensates requires models that resolve (i) local, chemistry specific contacts controlling β registry and (ii) mesoscale phase behavior and cluster coalescence on microsecond timescales—capabilities beyond single resolution models. We present a hybrid united atom/coarse grained (UA–CG) force field coupling a PACE UA peptide model with the MARTINI CG framework. Cross resolution nonbonded parameters are first optimized against all atom side chain potentials of mean force to balance the relative strength between different types of interactions and then refined through universal parameter scaling by matching radius of gyration distributions for specific systems using. We applied this approach to simulate a recently reported model system comprising the LVFFAR₉ peptide that can co-assemble into amyloid fibrils via liquid–liquid phase separation. Our ten-microsecond simulations reveal rapid droplet formation populated by micelle like nanostructures with its inner core composed of LVFF clusters. The nanostructures can further fuse but the fusion is reaction-limited due to an electrostatic coalescence barrier. β structures emerge once clusters exceed ~10 peptides, and the LVFFAR₉ fraction modulates amyloid polymorphism, reversing parallel versus antiparallel registry at lower LVFFAR₉. These detailed insights generated from long simulations highlight the promise of our hybrid UA–CG strategy in investigating the molecular mechanism of condensate aging. Full article

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms—insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features. Full article

Liquid–liquid phase separation (LLPS) is a fundamental biophysical process in which proteins and nucleic acids dynamically demix from the cellular milieu to form membraneless organelles (MLO) with liquid-like properties. Environmental cues, such as light, temperature fluctuations, and pathogen interactions, induce LLPS of fungal proteins with intrinsically disordered regions (IDRs) or multimerization domains, thereby regulating fungal hyphal growth, sexual reproduction, pathogenesis, and adaptation. Recently, LLPS has emerged as a powerful tool for biomolecular research, innovative biotechnological application, biosynthesis and metabolic engineering. This review focuses on the current advances in environmental cue-triggered fungal condensates assembled by LLPS, with a focus on their roles in regulating the fungal physical biology and cellular processes including transcription, RNA modification, translation, posttranslational modification process (PTM), transport, and stress response. It further discusses the strategies of engineering synthetic biomolecular condensates in microbial cell factories to enhance production and metabolic efficiency. Full article

Cellular organization relies on both membrane-bound organelles and membraneless biomolecular condensates formed through liquid–liquid phase separation. Recent discoveries reveal intricate coupling between lipid membrane organization and condensate assembly, reshaping our understanding of cellular compartmentalization. This review synthesizes multidisciplinary research using advanced techniques including super-resolution microscopy, fluorescence recovery after photobleaching, and in vitro reconstitution to examine lipid-condensate interactions. Lipid membranes serve as nucleation platforms that reduce critical concentrations for condensate formation by orders of magnitude through membrane anchoring and thermodynamic coupling, creating specialized microenvironments that substantially enhance enzymatic activities. Key regulatory mechanisms include phosphorylation-driven assembly and disassembly, membrane composition effects from cholesterol content and fatty acid saturation, and environmental factors such as calcium and pH. These interactions drive signal transduction through receptor clustering, membrane trafficking via organized domains, and stress responses through protective condensate formation. Dysregulation of lipid-condensate coupling, including aberrant phase transitions and membrane dysfunction, underlies metabolic disorders and neurodegenerative diseases. This coupling represents a fundamental organizing principle with significant therapeutic potential. Current challenges include developing quantitative methods for characterizing condensate dynamics in complex cellular environments and translating molecular mechanisms into clinical applications. Future progress requires interdisciplinary approaches combining advanced experimental techniques, computational modeling, and standardized protocols to advance both fundamental understanding and therapeutic innovations. Full article

Carbyne-containing materials offer significant potential for biosensor applications due to their unique chemical and mechanical properties. In this study, carbyne-enriched carbon coatings deposited on SiO₂/Si chips using ion-assisted pulse-plasma deposition were evaluated for the first time as substrates for optical biosensing. At first, the carbyne-enriched coatings were characterized by X-ray photoelectron spectroscopy, Raman spectroscopy, Atomic Force Microscopy, and the sessile drop method to assess their composition, structure, and wettability. After that, chips with carbyne-enriched coatings were modified with biomolecules through physical absorption or covalent bonding, and the respective biomolecular interactions were monitored in real-time by White Light Reflectance Spectroscopy (WLRS). In both cases, SiO₂/Si chips modified with an aminosilane were used as reference substrates. Physical adsorption was tested through immobilization of an antibody against C-reactive protein (CRP) to enable its immunochemical detection, whereas covalent bonding was tested through coupling of biotin and monitoring its reaction with streptavidin. It was found that the carbyne-enriched carbon-coated chips retained both their antibody adsorption capability and their covalent bonding ability for over 18 months, while the modified with aminosilane SiO₂/Si chips lost 90% of their antibody adsorption capacity and covalent bonding ability after two months of storage. These findings highlight the strong potential of carbyne-enriched carbon-coated chips as robust biosensing substrates, with applications extending beyond WLRS. Full article

Electric fields are emerging as powerful tools to actively regulate biomolecular interactions at biointerfaces. In this study, we investigated how varying electric field strengths (0–100 mV/mm) influence the interfacial interaction between human serum albumin (HSA) and six tyrosine kinase inhibitors (TKIs): imatinib, bosutinib, dasatinib, nilotinib, ponatinib, and radotinib. Using atomic force microscopy (AFM), we quantified changes in adhesion force, specific (F_i) and non-specific (F₀) force, friction behavior, and protein morphology. Increasing field strength led to significant reductions in adhesion force (22–47%), F_i (27–44%), F₀ (38–53%), friction force (38–67%) and constant-load friction force (43–54%), along with decreased protein average surface height and roughness, indicating electric field-induced molecular compaction and interface smoothing. Notably, more hydrophobic TKIs showed greater responsiveness. These findings highlight the potential of electric fields to modulate protein–drug interactions in a controllable manner, offering a new strategy for the development of electrically tunable drug delivery systems and smart biomedical interfaces. Full article

Biomolecular condensates (BCs), formed through liquid–liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies. Full article

Ultrahigh dose rate (UHDR) radiotherapy, also known as FLASH radiotherapy (FLASH-RT), has shown potential for increasing tumor control while sparing normal tissue. In parallel, gold nanoparticles (GNPs) have been extensively explored as radiosensitizers due to their high atomic number and ability to enhance the generation of reactive oxygen species (ROS) through water radiolysis. In this study, we investigate the synergistic effects of UHDR electron beams and GNP-mediated radiosensitization using Monte Carlo (MC) simulations based on the Geant4-DNA code. A spherical water phantom with embedded GNPs of varying sizes (5–100 nm) was irradiated using pulsed electron beams (100 keV and 1 MeV) at dose rates of 60, 100, and 150 Gy/s. The chemical yield of ROS near the GNPs was quantified and compared to an equivalent water nanoparticle model, and the yield enhancement factor (YEF) was used to evaluate radiosensitization. Results demonstrated that YEF increased with smaller GNP sizes and at lower UHDR, particularly for 1 MeV electrons. A maximum YEF of 1.25 was observed at 30 nm from the GNP surface for 5 nm particles at 60 Gy/s. The elevated ROS concentration near GNPs under FLASH conditions is expected to intensify DNA damage, especially double-strand breaks, due to increased hydroxyl radical interactions within nanometric distances of critical biomolecular targets. These findings highlight the significance of nanoparticle size and beam parameters in optimizing ROS production for FLASH-RT. The results provide a computational basis for future experimental investigations into the combined use of GNPs and UHDR beams in nanoparticle-enhanced radiotherapy. Full article

Polymers and polymer composites offer versatile possibilities for engineering the physico-chemical properties of materials on micro- and macroscopic scales. This review provides an overview of polymeric and polymer-decorated particles that can serve as drug-delivery vectors: linear polymers, star polymers, diblock-copolymer micelles, polymer-grafted nanoparticles, polymersomes, stealth liposomes, microgels, and biomolecular condensates. The physico-chemical interactions between the delivery vectors and biological cells range from chemical interactions on the molecular scale to deformation energies on the particle scale. The focus of this review is on the structure and elastic properties of these particles, as well as their circulation in blood and cellular uptake. Furthermore, the effects of polymer decoration in vivo (e.g., of glycosylated plasma membranes, cortical cytoskeletal networks, and naturally occurring condensates) on drug delivery are discussed. Full article

We present a dual biosensing strategy integrating Quartz Crystal Microbalance (QCM) and Surface-Enhanced Raman Spectroscopy (SERS) for the quantitative and molecular-specific detection of FKBP12. Silver nanodendritic arrays were electrodeposited onto QCM sensors, optimized for SERS enhancement using Rhodamine 6G, and functionalized with a custom-designed receptor to selectively capture FKBP12. QCM measurements revealed a two-step Langmuir adsorption behavior, enabling sensitive mass quantification with a low limit of detection. Concurrently, in situ SERS analysis on the same sensor provided vibrational fingerprints of FKBP12, resolved through comparative studies of the free protein, surface-bound receptor, and surface-bound receptor–protein complex. Ethanol-induced denaturation confirmed protein-specific peaks, while shifts in receptor vibrational modes—linked to FKBP12 binding—demonstrated dynamic molecular interactions. A ratiometric parameter, derived from key peak intensities, served as a robust, concentration-dependent signature of complex formation. This platform bridges quantitative (QCM) and structural (SERS) biosensing, offering real-time mass tracking and conformational insights. The nanodendritic substrate’s dual functionality, combined with the receptor’s selectivity, advances label-free protein detection for applications in drug diagnostics, with potential adaptability to other target analytes. Full article

This study aimed to evaluate the anticancer activity of lamellar alkaloid derivatives extracted from the tunicate Didemnum abradatum from Moucha Island (Djibouti), focusing on their antiviability against human cell lines and using biocomputational analyses via the Integrated Biomolecular Profiling and Mechanism Evaluation (IBProME) method to understand their mechanisms of action. Two alkaloids were isolated, lamellarin D and lamellarin T, whose structures were confirmed by state-of-the-art analytical techniques. Cell viability tests were performed on PC3, A549 and JIMT-T1 cell lines, and IBProME analyses were used to predict their interactions with p53 protein and evaluate their toxicological and pharmacokinetic profiles. The results showed that lamellarin D was particularly effective against prostate and lung cancer cells, with respective IC₅₀ values of 5.25 µg/mL and 8.64 µg/mL, close to those of doxorubicin. In contrast, lamellarin T showed less marked activity but remains promising. Computational analyses via IBProME highlighted differences in chemical reactivity between the two compounds, with lamellarin D being more reactive. Toxicity tests revealed that lamellarin D exhibited lower acute toxicity than lamellarin T. In terms of pharmacokinetic properties, both molecules showed low absorption and moderate bioavailability, although lamellarin T displayed more marked lipophilicity. These results suggest that lamellars, particularly lamellarin D, have therapeutic potential for the treatment of certain types of cancer. Full article

Background/Objectives: Understanding the stabilization mechanisms of amino acid conformations in different solvent environments is crucial for elucidating biomolecular interactions and crystallization processes. This study presents a comprehensive computational investigation of glycine, the simplest amino acid, in both its canonical and zwitterionic forms when interacting with dimethyl sulfoxide (DMSO) molecules. Methods: Using density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level with empirical dispersion corrections, we examined the conformational landscape of glycine–DMSO clusters with one and two DMSO molecules, as well as implicit solvent calculations, and compared them with analogous water clusters. Results: Our results demonstrate that while a single water molecule is insufficient to stabilize the zwitterionic form of glycine, one DMSO molecule successfully stabilizes this form through specific interactions between the S=O and the methyl groups of DMSO and the NH₃⁺ and the oxoanion group of zwitterionic glycine, respectively. Topological analysis of the electron density using QTAIM and NCI methods reveals the nature of these interactions. When comparing the relative stability between canonical and zwitterionic forms, we found that two DMSO molecules significantly reduce the energy gap to approximately 12 kJ mol⁻¹, suggesting that increasing DMSO coordination could potentially invert this stability. Implicit solvent calculations indicate that in pure DMSO medium, the zwitterionic form becomes more stable below 150 K, while remaining less stable at room temperature, contrasting with aqueous environments where the zwitterionic form predominates. Conclusions: These findings provide valuable insights into DMSO’s unique role in biomolecular stabilization and have implications for protein crystallization protocols where DMSO is commonly used as a co-solvent. Full article

Intrinsically disordered regions (IDRs), defined as protein segments lacking stable tertiary structures, are ubiquitously present in the human proteome and enriched with disease-associated mutations. IDRs harbor molecular recognition features (MoRFs) and post-translational modification sites (e.g., phosphorylation), enabling dynamic intermolecular interactions through conformational plasticity. Furthermore, IDRs drive liquid–liquid phase separation (LLPS) of biomacromolecules via multivalent interactions such as electrostatic attraction and pi–pi interactions, generating biomolecular condensates that are essential throughout the cellular lifecycle. These condensates separate intracellular space, forming a physical barrier to avoid interference between other molecules, thereby improving reaction specificity and efficiency. As a dynamically equilibrated process, LLPS formation and maintenance are regulated by multiple factors, endowing the condensates with rapid responsiveness to environmental cues and functional versatility in modulating diverse signaling cascades. Consequently, disruption of LLPS homeostasis can derail its associated biological processes, ultimately contributing to disease pathogenesis. Moreover, precisely because liquid–liquid phase separation (LLPS) is co-regulated by multiple factors, it may provide novel insights into the pathogenic mechanisms of disorders such as autism spectrum disorder (ASD), which result from the cumulative effects of multiple etiological factors. Full article

We report on the synthesis and characterization of a novel fluorenyl-methoxycarbonyl (Fmoc)-containing thioxo-triazole-bearing dipeptide 5, evaluated for potential therapeutic applications. The compound was tested for its antioxidant and antimicrobial properties, demonstrating significant effects in scavenging reactive oxygen species (ROS) and inhibiting microbial growth, particularly when combined with plant extracts from an endemic Peonia species from the Caucasus. Circular dichroism (CD) binding studies with bovine serum albumin (BSA) and calf thymus DNA revealed important interactions, suggesting the dipeptide’s potential in biomedically relevant conditions that involve DNA modulation. Molecular docking and CD spectra deconvolution provided additional insights into the binding mechanisms and structural characteristics of the formed complexes with the biomolecular targets. The Fmoc group enhances the dipeptide’s lipophilicity, which may facilitate its interaction with cellular membranes, supporting efficient drug delivery. A computational evaluation at the ωB97XD/aug-cc-pVDZ level of theory was carried out, confirming the experimental results and revealing a powerful potential of the peptide as an antioxidant, through FMOs, MEP analysis, and antioxidant mechanism assessments. Together, these findings suggest that this dipeptide could be valuable as an antimicrobial and antioxidant agent, with potential applications in pathologies involving oxidative stress, DNA modulation, and microbial infections. Full article

This article presents a comprehensive overview of recent advancements in photonic crystal fiber (PCF)-based sensors, with a particular focus on the surface plasmon resonance (SPR) phenomenon for biosensing. With their ability to modify core and cladding structures, PCFs offer exceptional control over light guidance, dispersion management, and light confinement, making them highly suitable for applications in refractive index (RI) sensing, biomedical imaging, and nonlinear optical phenomena such as fiber tapering and supercontinuum generation. SPR is a highly sensitive optical phenomenon, which is widely integrated with PCFs to enhance detection performance through strong plasmonic interactions at metal–dielectric interfaces. The combination of PCF and SPR technologies has led to the development of innovative sensor geometries, including D-shaped fibers, slotted-air-hole structures, and internal external metal coatings, each optimized for specific sensing goals. These PCF-SPR-based sensors have shown promising results in detecting biomolecular targets such as excess cholesterol, glucose, cancer cells, DNA, and proteins. Furthermore, this review provides an in-depth analysis of key design parameters, plasmonic materials, and sensor models used in PCF-SPR configurations, highlighting their comparative performance metrics and application prospects in medical diagnostics, environmental monitoring, and chemical analysis. Thus, an exhaustive analysis of various sensing parameters, plasmonic materials, and sensor models used in PCF-SPR sensors is presented and explored in this article. Full article