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    Computational modeling of intrinsically disordered and phase-separated protein states
    (Elsevier, 2024) Coskuner-Weber, Orkid; Uversky, Vladimir N.
    Intrinsically disordered proteins possess ensembles of conformations and lack stable three-dimensional structures. Phase separation is defined as a phenomenon in which proteins and biomolecules, often including intrinsically disordered proteins, separate from the surrounding solution to form membraneless compartments in the cell. Here, we describe various computational methods and algorithms for studying intrinsically disordered proteins and phase-separated protein states. The methods and algorithms described herein include molecular dynamics and Monte Carlo simulations, machine learning with molecular dynamics, coarse-grained simulations, and bioinformatics. © 2025 Elsevier Inc. All rights reserved.
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    Disordered peptide-based design of intrinsically disordered polymers for biomedical applications
    (Taylor & Francis Ltd, 2025) Coskuner-Weber, Orkid; Cayli, Fatma Nilsu; Uversky, Vladimir N.
    In the fields of biology and medicine, the development of synthetic polymers that emulate the unique conformational characteristics of intrinsically disordered proteins (IDPs) is of significant interest due to their exceptional structural and conformational versatility. The inherent flexibility of IDPs, arising from their absence of stable three-dimensional structures, enhances their capacity for self-organization, thereby rendering them advantageous for diverse biomedical applications. Intrinsically disordered synthetic polymers hold considerable promise in areas such as drug delivery systems, organ transplantation, artificial organ design, and immune system compatibility. However, advancing the synthesis and characterization methodologies for these polymers, which are derived from the properties of IDPs, remains a critical challenge. This article presents our design strategies for creating intrinsically disordered synthetic polymers tailored for biomedical use. These design methodologies are informed by the attributes of intrinsically disordered proteins and incorporate disorder-promoting oligopeptides.
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    Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10
    (Bentham Science Publ Ltd, 2024) Alici, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Coskuner-Weber, Orkid
    Introduction The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10Q108P proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.Method This study presents the foundational characterization of the structural features of CHCHD10Q108P and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses.Result Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology.Conclusion The reported structural properties hold promise for informing the development of more effective treatments for ALS.
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    Electromagnetic radiation and biophoton emission in neuronal communication and neurodegenerative diseases
    (Pergamon-Elsevier Science Ltd, 2025) Erboz, Aysin; Kesekler, Elif; Gentili, Pier Luigi; Uversky, Vladimir N.; Coskuner-Weber, Orkid
    The intersection of electromagnetic radiation and neuronal communication, focusing on the potential role of biophoton emission in brain function and neurodegenerative diseases is an emerging research area. Traditionally, it is believed that neurons encode and communicate information via electrochemical impulses, generating electromagnetic fields detectable by EEG and MEG. Recent discoveries indicate that neurons may also emit biophotons, suggesting an additional communication channel alongside the regular synaptic interactions. This dual signaling system is analyzed for its potential in synchronizing neuronal activity and improving information transfer, with implications for brain-like computing systems. The clinical relevance is explored through the lens of neurodegenerative diseases and intrinsically disordered proteins, where oxidative stress may alter biophoton emission, offering clues for pathological conditions, such as Alzheimer's and Parkinson's diseases. The potential therapeutic use of Low-Level Laser Therapy (LLLT) is also examined for its ability to modulate biophoton activity and mitigate oxidative stress, presenting new opportunities for treatment. Here, we invite further exploration into the intricate roles the electromagnetic phenomena play in brain function, potentially leading to breakthroughs in computational neuroscience and medical therapies for neurodegenerative diseases.
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    Key genes and pathways in the molecular landscape of pancreatic ductal adenocarcinoma: A bioinformatics and machine learning study
    (Elsevier Sci Ltd, 2024) Eyuboglu, Sinan; Alpsoy, Semih; Uversky, Vladimir N.; Coskuner-Weber, Orkid
    Pancreatic ductal adenocarcinoma (PDAC) is recognized for its aggressive nature, dismal prognosis, and a notably low five-year survival rate, underscoring the critical need for early detection methods and more effective therapeutic approaches. This research rigorously investigates the molecular mechanisms underlying PDAC, with a focus on the identification of pivotal genes and pathways that may hold therapeutic relevance and prognostic value. Through the construction of a protein-protein interaction (PPI) network and the examination of differentially expressed genes (DEGs), the study uncovers key hub genes such as CDK1, KIF11, and BUB1, demonstrating their substantial role in the pathogenesis of PDAC. Notably, the dysregulation of these genes is consistent across a spectrum of cancers, positing them as potential targets for wide-ranging cancer therapeutics. This study also brings to the fore significant genes encoding intrinsically disordered proteins, in particular GPRC5A and KRT7, unveiling promising new pathways for therapeutic intervention. Advanced machine learning techniques were harnessed to classify PDAC patients with high accuracy, utilizing the key genetic markers as a dataset. The Support Vector Machine (SVM) model leveraged the hub genes to achieve a sensitivity of 91 % and a specificity of 85 %, while the RandomForest model notched a sensitivity of 91 % and specificity of 92.5 %. Crucially, when the identified genes were cross-referenced with TCGA-PAAD clinical datasets, a tangible correlation with patient survival rates was discovered, reinforcing the potential of these genes as prognostic biomarkers and their viability as targets for therapeutic intervention. This study's findings serve as a potent testament to the value of molecular analysis in enhancing the understanding of PDAC and in advancing the pursuit for more effective diagnostic and treatment strategies.
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    Thermoresponsive intrinsically disordered protein polymers
    (Elsevier, 2024) Uversky, Vladimir N.; Tripathi, Timir; Coskuner-Weber, Orkid
    Thermoresponsive intrinsically disordered protein polymers (TIDPPs) are a unique class of biopolymers that lack a fixed three-dimensional structure under physiological conditions and exhibit temperature-responsive behavior. These properties are primarily driven by their amino acid composition and sequence, which lead to changes in solubility and phase transitions at a critical temperature known as the lower critical solution temperature (LCST). TIDPPs transition from a soluble state below the LCST to an aggregated state above it, facilitating applications in drug delivery, tissue engineering, and smart biomaterials. The reversible phase behavior allows for precise control over drug release, targeted delivery, and scaffold properties, enhancing therapeutic efficacy and tissue regeneration. TIDPPs can be engineered to achieve specific LCST values, which make them highly versatile for various biomedical and industrial applications. Their biocompatibility and biodegradability further make them suitable for use in clinical settings, minimizing risks of adverse immune reactions. The field continues to explore the potential of TIDPPs with advanced bioengineering techniques for developing next-generation materials with tunable properties responsive to environmental stimuli. © 2025 Elsevier Inc. All rights reserved.