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Öğe Alanine scanning effects on the biochemical and viophysical properties of intrinsically disordered proteins: a case study of the histidine to alanine mutations in amyloid-beta(42)(Amer Chemical Soc, 2019) Weber, Orkide Coşkuner; Uversky, Vladimir N.Alanine scanning is a tool in molecular biology that is commonly used to evaluate the contribution of a specific amino acid residue to the stability and function of a protein. Additionally, this tool is also used to understand whether the side chain of a specific amino acid residue plays a role in the protein's bioactivity. Furthermore, computational alanine scanning methods are utilized to predict the thermodynamic properties of proteins. These studies are utilized with the assumption that the biochemical and biophysical properties of a protein do not change with alanine scanning. Our study was dedicated to analyze the effect of alanine scanning on the biochemical and biophysical properties of intrinsically disordered proteins. To this end, we studied the impact of widely used histidine to alanine mutations in amyloid-beta (A beta). We found that the secondary and tertiary contacts, salt bridge formations, and thermodynamic properties, as well as disorder propensities and aggregation predisposition of A beta, are impacted by the single and triple point histidine to alanine mutations. Experimental and computational studies employing the alanine scanning technique for mutating histidine to alanine in the analysis of intrinsically disordered proteins have to consider these effects.Öğe BMP-2 and BMP-9 binding specificities with ALK-3 in aqueous solution with dynamics(Elsevier Science Inc, 2017) Weber, Orkide Coşkuner; Uversky, Vladimir N.Signal ligands of the transforming growth factor-beta (TGF-beta) superfamily include the bone morphogenetic proteins (BMPs). BMPs bind to type I and type II serine-threonine kinase receptors and trigger the transphosphorylation cascade, wherein the active type II receptor phosphorylates the inactive type I receptor. This process further activates the cytoplasmic effectors of the pathway, such as SMAD proteins, which are homologs of both the Drosophila protein MAD (mothers against decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size). Even though biological and medicinal studies have been performed on these complex species, we currently do not know the underlying molecular mechanisms of the signal ligand interactions with the receptors. Detailed understanding of these interactions increases our knowledge about these proteins, and also can provide the lacking information for successful mutation experiments. This study focuses on the computational analysis of binding affinities and structural binding specificities of two different types of BMPs (BMP-2 and BMP-9) to the activin receptor-. like kinases (ALK-3) in solution. For studying the binding characteristics of BMP-2 or BMP-9 with ALK-3 in aqueous solution, we performed extensive molecular dynamics simulations coupled with thermodynamic calculations. The calculated thermodynamic properties show that the BMP-2/ALK-3 complex is thermodynamically more stable than a possible BMP-9/ALK-3 species in aqueous solution. The binding free energies indicate that ALK-3 preferably binds to BMP-2 instead of BMP-9. The structural analysis shows that ALK-3 binding with BMP-2 occurs in a perfectly symmetry pathway, whereas this symmetry is lost for possible ALK-3 interactions with BMP-9. The Phe49 to Va170 loop region of BMP-2 presents strong inter-molecular interactions with ALK-3. On the other hand, BMP-9 presents weaker interactions with ALK-3 via a non-continuous sequence. ALK-3-binding region of BMP-2 corresponds to the region predicted to be flexible by our intrinsic disorder analysis, whereas the related region of BMP-9 is expected to be noticeably less flexible. This study proposes that mutating the BMP-9 with the partial Phe49 to Va170 sequence of BMP-2 can help to increase the reactivity of BMP-9 towards stable ALK-3 binding, which in turn has the potential to develop new signaling pathways for improving the formation of tissues and to prevent or treat severe diseases. Furthermore, this study also demonstrates the usefulness of theoretical physical chemistry tools, such as molecular dynamics simulations and the ProtMet simulation software package in the structural characterization of the TGF-beta superfamily proteins. (C) 2017 Elsevier Inc. All rights reserved.Öğe Challenges and limitations in the studies of glycoproteins: A computational chemist's perspective(WILEY, 2021) Ballı, Öykü İrem; Uversky, Vladimir N.; Durdağı, Serdar; Weber, Orkide CoşkunerExperimenters face challenges and limitations while analyzing glycoproteins due to their high flexibility, stereochemistry, anisotropic effects, and hydration phenomena. Computational studies complement experiments and have been used in characterization of the structural properties of glycoproteins. However, recent investigations revealed that computational studies face significant challenges as well. Here, we introduce and discuss some of these challenges and weaknesses in the investigations of glycoproteins. We also present requirements of future developments in computational biochemistry and computational biology areas that could be necessary for providing more accurate structural property analyses of glycoproteins using computational tools. Further theoretical strategies that need to be and can be developed are discussed herein.Öğe Chapter 33 - Methods to study the effect of solution variables on the conformational dynamics of intrinsically disordered proteins(Elsevier Academic Press, 2022) Alıcı, Hakan; Uversky, Vladimir N.; Coşkuner Weber, Orkid; Hasekioğlu, Orkun[Özet yok]Öğe 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.Öğe Current stage and future perspectives for homology modeling, molecular dynamics simulations, machine learning with molecular dynamics, and quantum computing for intrinsically disordered proteins and proteins with intrinsically disordered regions(2024) Coşkuner Weber, Orkid; Uversky, Vladimir N.The structural ensembles of intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) cannot be easily characterized using conventional experimental techniques. Computational techniques complement experiments and provide useful insights into the structural ensembles of IDPs and proteins with IDRs. Herein, we discuss computational techniques such as homology modeling, molecular dynamics simulations, machine learning with molecular dynamics, and quantum computing that can be applied to the studies of IDPs and hybrid proteins with IDRs. We also provide useful future perspectives for computational techniques that can be applied to IDPs and hybrid proteins containing ordered domains and IDRs.Öğe 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.Öğe 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, OrkidIntroduction 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.Öğe Effects of the Jokela type of spinal muscular atrophy-relatedG66V mutation on the structural ensemble characteristics ofCHCHD10(2023) Alıcı, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Coşkuner Weber, OrkidThe G66V pathological variant of the coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), mitochondrial, plays a role in Jokela type spinalmuscular atrophy. The wild-type and G66V mutant-type CHCHD10 proteins containintrinsically disordered regions, and therefore, their structural ensemble studies havebeen experiencing difficulties using conventional tools. Here, we show our resultsregarding the first characterization of the structural ensemble characteristics of theG66V mutant form of CHCHD10 and the first comparison of these characteristicswith the structural ensemble properties of wild-type CHCHD10. We find that thestructural properties, potential of mean force surfaces, and principal component anal-ysis show stark differences between these two proteins. These results are importantfor a better pathology, biochemistry and structural biology understanding ofCHCHD10 and its G66V genetic variant and it is likely that these reported structuralproperties are important for designing more efficient treatments for the Jokela typeof spinal muscular atrophy disease.Öğe 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, OrkidThe 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.Öğe Epitope region identification challenges of intrinsically disordered proteins in neurodegenerative diseases: Secondary structure dependence of alpha-synuclein on simulation techniques and force field parameters(Wiley, 2020) Mandacı, Sunay Yağız; Çalışkan, Murat; Sarıaslan, M. Furkan; Uversky, Vladimir N.; Weber, Orkide CoşkunerDue to fast aggregation processes of many disordered proteins in neurodegenerative diseases, it is difficult to study their epitope regions at the monomeric and oligomeric levels. Computer simulations complement experiments and have been used to identify the epitope regions of proteins. Residues that adopt beta-sheet conformation play a central role in the oligomerization and aggregation mechanisms of such proteins, including alpha-synuclein, which is at the center of Parkinson's and Alzheimer's diseases. In this study, we simulated the monomeric alpha-synuclein protein in an aqueous environment to evaluate its secondary structure properties, including beta-sheet propensity, and radius of gyration by replica exchange molecular dynamics simulations. We also obtained the molecular dynamics simulation trajectories of alpha-synuclein that were conducted using various force field parameters by the David E. Shaw group. Using these trajectories, we calculated the impacts of force field parameters on alpha-synuclein secondary structure properties and radius of gyration values and obtained results are compared with our data from REMD simulations. This study shows that the chosen force field parameters and computer simulation techniques effect the predicted secondary structure properties and radius of gyration values of alpha-synuclein in water. Herewith, we illustrate the challenges in epitope region identification of intrinsically disordered proteins in neurodegenerative diseases by current computer simulations.Öğe From quantum mechanics, classical mechanics, and bioinformatics to artificial intelligence studies in neurodegenerative diseases(Springer, 2022) Habiboğlu, Mehmet Gökhan; Coşkuner Weber, Orkid; Uversky, Vladimir N.; Teplow, DavidThe amyloid ?-protein is an intrinsically disordered protein that has the potential to assemble into myriad structures, including oligomers and fibrils. These structures are neurotoxic and are thought to initiate a cascade of events leading to Alzheimer’s disease. Understanding this pathogenetic process and elucidating targets for drug therapy depends on elucidation of the structural dynamics of A? assembly. In this chapter, we describe work packages required to determine the three-dimensional structures of A? and of smaller bioactive fragments thereof, which may be important in AD pathogenesis. These packages include density functional theory, Car–Parrinello molecular dynamics simulations, temperature-dependent replica exchange molecular dynamics simulations, disorder predictors based on bioinformatics, and neural network deep learning.Öğe Frontotemporal dementia-related V57E mutation impairs mitochondrial function and alters the structural properties of CHCHD10(2023) Alıcı, Hakan; Uversky, Vladimir N.; Liu, Tian; Kang, David E.; Woo, Junga Alexa; Coşkuner Weber, OrkidThe V57E pathological variant of the mitochondrial coiled-coil-helix–coiled-coil-helix domain-containing protein 10 (CHCHD10) plays a role in frontotemporal dementia. The wild-type and V57E mutant CHCHD10 proteins contain intrinsically disordered regions, and therefore, these regions hampered structural characterization of these proteins using conventional experimental tools. For the first time in the literature, we represent that the V57E mutation is pathogenic to mitochondria as it increases mitochondrial superoxide and impairs mitochondrial respiration. In addition, we represent here the structural ensemble properties of the V57E mutant CHCHD10 and describe the impacts of V57E mutation on the structural ensembles of wild-type CHCHD10 in aqueous solution. We conducted experimental and computational studies for this research. Namely, MitoSOX Red staining and Seahorse Mito Stress experiments, atomic force microscopy measurements, bioinformatics, homology modeling, and multiple-run molecular dynamics simulation computational studies were conducted. Our experiments show that the V57E mutation results in mitochondrial dysfunction, and our computational studies present that the structural ensemble properties of wild-type CHCHD10 are impacted by the frontotemporal dementia-associated V57E genetic mutation.Öğe Insights into the molecular mechanisms of Alzheimer's and Parkinson's diseases with molecular simulations: understanding the roles of artificial and pathological missense mutations in intrinsically disordered proteins related to pathology(Mdpi, 2018) Weber, Orkide Coşkuner; Uversky, Vladimir N.Amyloid-beta and alpha-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer's and Parkinson's disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid- and -synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer's and Parkinson's diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid- and -synuclein in relation to the pathologies of Alzheimer's and Parkinson's diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer's and Parkinson's diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid- and -synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid- and -synuclein, such as -structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer's and Parkinson's diseases. This information represents an important foundation for the successful and efficient drug design studies.Öğe Insights into the structural properties of SARS-CoV-2 main protease(Elsevier BV, 2022) Akbayrak, İbrahim Yağız; Çağlayan, Şule İrem; Kurgan, Lukasz; Uversky, Vladimir N.; Coşkuner Weber, OrkidSARS-CoV-2 is the infectious agent responsible for the coronavirus disease since 2019, which is the viral pneumonia pandemic worldwide. The structural knowledge on SARS-CoV-2 is rather limited. These limitations are also applicable to one of the most attractive drug targets of SARS-CoV-2 proteins – namely, main protease Mpro, also known as 3C-like protease (3CLpro). This protein is crucial for the processing of the viral polyproteins and plays crucial roles in interfering viral replication and transcription. In fact, although the crystal structure of this protein with an inhibitor was solved, Mpro conformational dynamics in aqueous solution is usually studied by molecular dynamics simulations without special sampling techniques. We conducted replica exchange molecular dynamics simulations on Mpro in water and report the dynamic structures of Mpro in an aqueous environment including root mean square fluctuations, secondary structure properties, radius of gyration, and end-to-end distances, chemical shift values, intrinsic disorder characteristics of Mpro and its active sites with a set of computational tools. The active sites we found coincide with the currently known sites and include a new interface for interaction with a protein partner.Öğe Intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases(Elsevier BV., 2022) Mirzanlı, Ozan; Coşkuner Weber, Orkid; Uversky, Vladimir N.Many diferent intrinsically disordered proteins and proteins with intrinsically disordered regions are associated with neurodegenerative diseases. These types of proteins including amyloid-?, tau, ?-synuclein, CHCHD2, CHCHD10, and G-protein coupled receptors are increasingly becoming evaluated as potential drug targets in the pharmaceutical-based treatment approaches. Here, we focus on the neurobiology of this class of proteins, which lie at the center of numerous neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Charcot–Marie–Tooth diseases, spinal muscular atrophy, and mitochondrial myopathy. Furthermore, we discuss the current treatment design strategies involving intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases. In addition, we emphasize that although the G-protein coupled receptors are traditionally investigated using structural biology-based models and approaches, current studies show that these receptors are proteins with intrinsically disordered regions and therefore they require new ways for their analysis.Öğe Intrinsically disordered proteins in various hypotheses on the pathogenesis of Alzheimer's and Parkinson's diseases(Elsevier Academic Press Inc, 2019) Weber, Orkide Coşkuner; Uversky, Vladimir N.Amyloid-beta (A beta) and alpha-synuclein (alpha S) are two intrinsically disordered proteins (IDPs) at the centers of the pathogenesis of Alzheimer's and Parkinson's diseases, respectively. Different hypotheses have been proposed for explanation of the molecular mechanisms of the pathogenesis of these two diseases, with these two IDPs being involved in many of these hypotheses. Currently, we do not know, which of these hypothesis is more accurate. Experiments face challenges due to the rapid conformational changes, fast aggregation processes, solvent and paramagnetic effects in studying these two IDPs in detail. Furthermore, pathological modifications impact their structures and energetics. Theoretical studies using computational chemistry and computational biology have been utilized to understand the structures and energetics of A beta and alpha S. In this chapter, we introduce A beta and alpha S in light of various hypotheses, and discuss different experimental and theoretical techniques that are used to study these two proteins along with their weaknesses and strengths. We suggest that a promising solution for studying A beta and alpha S at the center of varying hypotheses could be provided by developing new techniques that link quantum mechanics, statistical mechanics, thermodynamics, bioinformatics to machine learning. Such new developments could also lead to development in experimental techniques.Öğe Intrinsically disordered proteins in various hypotheses on the pathogenesis of Alzheimer’xxs and Parkinson’xxs diseases(Academic Press, 2019) Uversky, Vladimir N.; Coşkuner Weber, Orkid"Dancing protein clouds: Intrinsically disordered proteins in the norm and pathology" represents a set of selected studies on a variety of research topics related to intrinsically disordered proteins. Topics in this update include structural and functional characterization of several important intrinsically disordered proteins, such as 14-3-3 proteins and their partners, as well as proteins from muscle sarcomere; representation of intrinsic disorder-related concept of protein structure-function continuum; discussion of the role of intrinsic disorder in phenotypic switching; consideration of the role of intrinsically disordered proteins in the pathogenesis of neurodegenerative diseases and cancer; discussion of the roles of intrinsic disorder in functional amyloids; demonstration of the usefulness of the analysis of translational diffusion of unfolded and intrinsically disordered proteins; consideration of various computational tools for evaluation of functions of intrinsically disordered regions; and discussion of the role of shear stress in the amyloid formation of intrinsically disordered regions in the brain.Öğe Intrinsically disordered synthetic polymers in biomedical applications(Polymers, 2023) Yüce-Erarslan, Elif; Kasem, Haytam; Uversky, Vladimir N.; Coşkuner Weber, Orkid; Domb, Abraham (Avi) J.In biology and medicine, intrinsically disordered synthetic polymers bio-mimicking intrinsically disordered proteins, which lack stable three-dimensional structures, possess high structural/conformational flexibility. They are prone to self-organization and can be extremely useful in various biomedical applications. Among such applications, intrinsically disordered synthetic polymers can have potential usage in drug delivery, organ transplantation, artificial organ design, and immune compatibility. The designing of new syntheses and characterization mechanisms is currently required to provide the lacking intrinsically disordered synthetic polymers for biomedical applications bio-mimicked using intrinsically disordered proteins. Here, we present our strategies for designing intrinsically disordered synthetic polymers for biomedical applications based on bio-mimicking intrinsically disordered proteins.Öğe 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, OrkidPancreatic 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.
