39 results on '"Arthur O. Zalevsky"'
Search Results
2. Genomic signatures of recombination in a natural population of the bdelloid rotifer Adineta vaga
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Olga A. Vakhrusheva, Elena A. Mnatsakanova, Yan R. Galimov, Tatiana V. Neretina, Evgeny S. Gerasimov, Sergey A. Naumenko, Svetlana G. Ozerova, Arthur O. Zalevsky, Irina A. Yushenova, Fernando Rodriguez, Irina R. Arkhipova, Aleksey A. Penin, Maria D. Logacheva, Georgii A. Bazykin, and Alexey S. Kondrashov
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Science - Abstract
Ancient, asexual lineages are rare as a lack of recombination is usually an evolutionary dead end. Here, authors compare complete genomes of 11 individual bdelloid rotifers that suggest evidence of regular genetic exchange between individuals in a species that was previously thought to be asexual.
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- 2020
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3. Extracellular Vesicles in Chronic Demyelinating Diseases: Prospects in Treatment and Diagnosis of Autoimmune Neurological Disorders
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Leyla A. Ovchinnikova, Arthur O. Zalevsky, and Yakov A. Lomakin
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extracellular vesicle ,exosomes ,microvesicles ,EVs ,EAE ,biomarker ,Science - Abstract
Extracellular vesicles (EVs) represent membrane-enclosed structures that are likely to be secreted by all living cell types in the animal organism, including cells of peripheral (PNS) and central nervous systems (CNS). The ability to cross the blood-brain barrier (BBB) provides the possibility not only for various EV-loaded molecules to be delivered to the brain tissues but also for the CNS-to-periphery transmission of these molecules. Since neural EVs transfer proteins and RNAs are both responsible for functional intercellular communication and involved in the pathogenesis of neurodegenerative diseases, they represent attractive diagnostic and therapeutic targets. Here, we discuss EVs’ role in maintaining the living organisms’ function and describe deviations in EVs’ structure and malfunctioning during various neurodegenerative diseases.
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- 2022
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4. In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties
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Anton V. Malyshev, Iuliia A. Sukhanova, Alexander S. Zlobin, Vasilina R. Gedzun, Vsevolod V. Pavshintsev, Ekaterina V. Vasileva, Arthur O. Zalevsky, Igor I. Doronin, Nikita A. Mitkin, Andrey V. Golovin, Maxim L. Lovat, Georgy I. Kovalev, Yurii A. Zolotarev, Askar R. Kuchumov, Gennady A. Babkin, and Bernhard Luscher
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peptide drugs ,drug screening ,novel ligand ,NMDA receptor ,alpha(2)delta subunit ,computational approach ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABAA receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABAA receptors and α2δ. In silico docking studies of one of these peptides, LCGA-17, showed a high binding score for both GABAA receptors and α2δ, combined with anxiolytic-like properties in a Danio rerio behavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light–dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABAA receptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABAA receptors.
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- 2021
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5. Zinc Modulation of Neuronal Calcium Sensor Proteins: Three Modes of Interaction with Different Structural Outcomes
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Viktoriia E. Baksheeva, Philipp O. Tsvetkov, Arthur O. Zalevsky, Vasiliy I. Vladimirov, Neonila V. Gorokhovets, Dmitry V. Zinchenko, Sergei E. Permyakov, François Devred, and Evgeni Yu. Zernii
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neuronal calcium sensors ,EF-hand ,zinc ,Zn2+-binding proteins ,recoverin ,visinin-like protein-1 ,Microbiology ,QR1-502 - Abstract
Neuronal calcium sensors (NCSs) are the family of EF-hand proteins mediating Ca2+-dependent signaling pathways in healthy neurons and neurodegenerative diseases. It was hypothesized that the calcium sensor activity of NCSs can be complemented by sensing fluctuation of intracellular zinc, which could further diversify their function. Here, using a set of biophysical techniques, we analyzed the Zn2+-binding properties of five proteins belonging to three different subgroups of the NCS family, namely, VILIP1 and neurocalcin-δ/NCLD (subgroup B), recoverin (subgroup C), as well as GCAP1 and GCAP2 (subgroup D). We demonstrate that each of these proteins is capable of coordinating Zn2+ with a different affinity, stoichiometry, and structural outcome. In the absence of calcium, recoverin and VILIP1 bind two zinc ions with submicromolar affinity, and the binding induces pronounced conformational changes and regulates the dimeric state of these proteins without significant destabilization of their structure. In the presence of calcium, recoverin binds zinc with slightly decreased affinity and moderate conformational outcome, whereas VILIP1 becomes insensitive to Zn2+. NCALD binds Zn2+ with micromolar affinity, but the binding induces dramatic destabilization and aggregation of the protein. In contrast, both GCAPs demonstrate low-affinity binding of zinc independent of calcium, remaining relatively stable even at submillimolar Zn2+ concentrations. Based on these data, and the results of structural bioinformatics analysis, NCSs can be divided into three categories: (1) physiological Ca2+/Zn2+ sensor proteins capable of binding exchangeable (signaling) zinc (recoverin and VILIP1), (2) pathological Ca2+/Zn2+ sensors responding only to aberrantly high free zinc concentrations by denaturation and aggregation (NCALD), and (3) Zn2+-resistant, Ca2+ sensor proteins (GCAP1, GCAP2). We suggest that NCS proteins may therefore govern the interconnection between Ca2+-dependent and Zn2+-dependent signaling pathways in healthy neurons and zinc cytotoxicity-related neurodegenerative diseases, such as Alzheimer’s disease and glaucoma.
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- 2022
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6. Mechanism of Zn2+ and Ca2+ Binding to Human S100A1
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Viktoriia E. Baksheeva, Andrei Yu. Roman, Claude Villard, François Devred, Deborah Byrne, Dahbia Yatoui, Arthur O. Zalevsky, Alisa A. Vologzhannikova, Andrey S. Sokolov, Sergei E. Permyakov, Andrey V. Golovin, Gary S. Shaw, Philipp O. Tsvetkov, and Evgeni Yu. Zernii
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S100A1 ,zinc ,calcium ,ESI-MS ,ITC ,nanoDSF ,Microbiology ,QR1-502 - Abstract
S100A1 is a member of the S100 family of small ubiquitous Ca2+-binding proteins, which participates in the regulation of cell differentiation, motility, and survival. It exists as homo- or heterodimers. S100A1 has also been shown to bind Zn2+, but the molecular mechanisms of this binding are not yet known. In this work, using ESI-MS and ITC, we demonstrate that S100A1 can coordinate 4 zinc ions per monomer, with two high affinity (KD~4 and 770 nm) and two low affinity sites. Using competitive binding experiments between Ca2+ and Zn2+ and QM/MM molecular modeling we conclude that Zn2+ high affinity sites are located in the EF-hand motifs of S100A1. In addition, two lower affinity sites can bind Zn2+ even when the EF-hands are saturated by Ca2+, resulting in a 2Ca2+:S100A1:2Zn2+ conformer. Finally, we show that, in contrast to calcium, an excess of Zn2+ produces a destabilizing effect on S100A1 structure and leads to its aggregation. We also determined a higher affinity to Ca2+ (KD~0.16 and 24 μm) than was previously reported for S100A1, which would allow this protein to function as a Ca2+/Zn2+-sensor both inside and outside cells, participating in diverse signaling pathways under normal and pathological conditions.
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- 2021
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7. Disulfide Dimerization of Neuronal Calcium Sensor-1: Implications for Zinc and Redox Signaling
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Viktoriia E. Baksheeva, Alexey V. Baldin, Arthur O. Zalevsky, Aliya A. Nazipova, Alexey S. Kazakov, Vasiliy I. Vladimirov, Neonila V. Gorokhovets, François Devred, Pavel P. Philippov, Alexandr V. Bazhin, Andrey V. Golovin, Andrey A. Zamyatnin, Dmitry V. Zinchenko, Philipp O. Tsvetkov, Sergei E. Permyakov, and Evgeni Yu. Zernii
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EF-hand ,NCS family ,neuronal calcium sensor-1 ,disulfide dimerization ,GRK1 ,zinc ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Neuronal calcium sensor-1 (NCS-1) is a four-EF-hand ubiquitous signaling protein modulating neuronal function and survival, which participates in neurodegeneration and carcinogenesis. NCS-1 recognizes specific sites on cellular membranes and regulates numerous targets, including G-protein coupled receptors and their kinases (GRKs). Here, with the use of cellular models and various biophysical and computational techniques, we demonstrate that NCS-1 is a redox-sensitive protein, which responds to oxidizing conditions by the formation of disulfide dimer (dNCS-1), involving its single, highly conservative cysteine C38. The dimer content is unaffected by the elevation of intracellular calcium levels but increases to 10–30% at high free zinc concentrations (characteristic of oxidative stress), which is accompanied by accumulation of the protein in punctual clusters in the perinuclear area. The formation of dNCS-1 represents a specific Zn2+-promoted process, requiring proper folding of the protein and occurring at redox potential values approaching apoptotic levels. The dimer binds Ca2+ only in one EF-hand per monomer, thereby representing a unique state, with decreased α-helicity and thermal stability, increased surface hydrophobicity, and markedly improved inhibitory activity against GRK1 due to 20-fold higher affinity towards the enzyme. Furthermore, dNCS-1 can coordinate zinc and, according to molecular modeling, has an asymmetrical structure and increased conformational flexibility of the subunits, which may underlie their enhanced target-binding properties. In HEK293 cells, dNCS-1 can be reduced by the thioredoxin system, otherwise accumulating as protein aggregates, which are degraded by the proteasome. Interestingly, NCS-1 silencing diminishes the susceptibility of Y79 cancer cells to oxidative stress-induced apoptosis, suggesting that NCS-1 may mediate redox-regulated pathways governing cell death/survival in response to oxidative conditions.
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- 2021
- Full Text
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8. Reprogramming Extracellular Vesicles for Protein Therapeutics Delivery
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Leyla A. Ovchinnikova, Stanislav S. Terekhov, Rustam H. Ziganshin, Dmitriy V. Bagrov, Ioanna N. Filimonova, Arthur O. Zalevsky, and Yakov A. Lomakin
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extracellular vesicles ,exosomes ,EVs ,protein delivery ,nanocages ,VSV-G ,Pharmacy and materia medica ,RS1-441 - Abstract
Delivering protein therapeutics specifically into target cells and tissues is a promising avenue in medicine. Advancing this process will significantly enhance the efficiency of the designed drugs. In this regard, natural membrane-based systems are of particular interest. Extracellular vesicles (EVs), being the bilayer lipid particles secreted by almost all types of cells, have several principal advantages: biocompatibility, carrier stability, and blood–brain barrier penetrability, which make them a perspective tool for protein therapeutic delivery. Here, we evaluate the engineered genetically encoded EVs produced by a human cell line, which allow efficient cargo loading. In the devised system, the protein of interest is captured by self-assembling structures, i.e., “enveloped protein nanocages” (EPN). In their turn, EPNs are encapsulated in fusogenic EVs by the overexpression of vesicular stomatitis virus G protein (VSV-G). The proteomic profiles of different engineered EVs were determined for a comprehensive evaluation of their therapeutic potential. EVs loading mediated by bio-safe Fos–Jun heterodimerization demonstrates an increased efficacy of active cargo loading and delivery into target cells. Our results emphasize the outstanding technological and biomedical potential of the engineered EV systems, including their application in adoptive cell transfer and targeted cell reprogramming.
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- 2021
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9. Zinc Binds to RRM2 Peptide of TDP-43
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Andrey V. Golovin, Francois Devred, Dahbia Yatoui, Andrei Yu. Roman, Arthur O. Zalevsky, Remy Puppo, Regine Lebrun, Francoise Guerlesquin, and Philipp O. Tsvetkov
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TDP-43 ,zinc ,QM/MM ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Transactive response DNA and RNA binding protein 43 kDa (TDP-43) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP), which is involved in several steps of protein production including transcription and splicing. Its aggregates are frequently observed in motor neurons from amyotrophic lateral sclerosis patients and in the most common variant of frontotemporal lobar degeneration. Recently it was shown that TDP-43 is able to bind Zn2+ by its RRM domain. In this work, we have investigated Zn2+ binding to a short peptide 256–264 from C-terminus of RRM2 domain using isothermal titration calorimetry, electrospray ionization mass spectrometry, QM/MM simulations, and NMR spectroscopy. We have found that this peptide is able to bind zinc ions with a Ka equal to 1.6 × 105 M−1. Our findings suggest the existence of a zinc binding site in the C-terminal region of RRM2 domain. Together with the existing structure of the RRM2 domain of TDP-43 we propose a model of its complex with Zn2+ which illustrates how zinc might regulate DNA/RNA binding.
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- 2020
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10. Membrane Binding of Neuronal Calcium Sensor-1: Highly Specific Interaction with Phosphatidylinositol-3-Phosphate
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Viktoriia E. Baksheeva, Ekaterina L. Nemashkalova, Alexander M. Firsov, Arthur O. Zalevsky, Vasily I. Vladimirov, Natalia K. Tikhomirova, Pavel P. Philippov, Andrey A. Zamyatnin, Dmitry V. Zinchenko, Yuri N. Antonenko, Sergey E. Permyakov, and Evgeni Yu. Zernii
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neuronal calcium sensors ,neuronal calcium sensor-1 ,ncs-1 ,membrane binding ,n-terminal myristoylation ,myristoyl group ,phospholipid-binding proteins ,phosphoinositides ,phosphatidylinositol-3-phosphate ,pi3p ,Microbiology ,QR1-502 - Abstract
Neuronal calcium sensors are a family of N-terminally myristoylated membrane-binding proteins possessing a different intracellular localization and thereby targeting unique signaling partner(s). Apart from the myristoyl group, the membrane attachment of these proteins may be modulated by their N-terminal positively charged residues responsible for specific recognition of the membrane components. Here, we examined the interaction of neuronal calcium sensor-1 (NCS-1) with natural membranes of different lipid composition as well as individual phospholipids in form of multilamellar liposomes or immobilized monolayers and characterized the role of myristoyl group and N-terminal lysine residues in membrane binding and phospholipid preference of the protein. NCS-1 binds to photoreceptor and hippocampal membranes in a Ca2+-independent manner and the binding is attenuated in the absence of myristoyl group. Meanwhile, the interaction with photoreceptor membranes is less dependent on myristoylation and more sensitive to replacement of K3, K7, and/or K9 of NCS-1 by glutamic acid, reflecting affinity of the protein to negatively charged phospholipids. Consistently, among the major phospholipids, NCS-1 preferentially interacts with phosphatidylserine and phosphatidylinositol with micromolar affinity and the interaction with the former is inhibited upon mutating of N-terminal lysines of the protein. Remarkably, NCS-1 demonstrates pronounced specific binding to phosphoinositides with high preference for phosphatidylinositol-3-phosphate. The binding does not depend on myristoylation and, unexpectedly, is not sensitive to the charge inversion mutations. Instead, phosphatidylinositol-3-phosphate can be recognized by a specific site located in the N-terminal region of the protein. These data provide important novel insights into the general mechanism of membrane binding of NCS-1 and its targeting to specific phospholipids ensuring involvement of the protein in phosphoinositide-regulated signaling pathways.
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- 2020
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11. Mitochondria as a Source and a Target for Uremic Toxins
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Vasily A. Popkov, Denis N. Silachev, Arthur O. Zalevsky, Dmitry B. Zorov, and Egor Y. Plotnikov
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uremia ,oxidative stress ,mitochondria ,kidney injury ,toxins ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins.
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- 2019
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12. Putative Mechanisms Underlying High Inhibitory Activities of Bimodular DNA Aptamers to Thrombin
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Elena G. Zavyalova, Valeriia A. Legatova, Rugiya Sh. Alieva, Arthur O. Zalevsky, Vadim N. Tashlitsky, Alexander M. Arutyunyan, and Alexey M. Kopylov
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DNA aptamer ,G-quadruplex ,conformational polymorphism ,thermodynamics ,thrombin ,structure–activity relationship ,Microbiology ,QR1-502 - Abstract
Nucleic acid aptamers are prospective molecular recognizing elements. Similar to antibodies, aptamers are capable of providing specific recognition due to their spatial structure. However, the apparent simplicity of oligonucleotide folding is often elusive, as there is a balance between several conformations and, in some cases, oligomeric structures. This research is focused on establishing a thermodynamic background and the conformational heterogeneity of aptamers taking a series of thrombin DNA aptamers having G-quadruplex and duplex modules as an example. A series of aptamers with similar modular structures was characterized with spectroscopic and chromatographic techniques, providing examples of the conformational homogeneity of aptamers with high inhibitory activity, as well as a mixture of monomeric and oligomeric species for aptamers with low inhibitory activity. Thermodynamic parameters for aptamer unfolding were calculated, and their correlation with aptamer functional activity was found. Detailed analysis of thrombin complexes with G-quadruplex aptamers bound to exosite I revealed the similarity of the interfaces of aptamers with drastically different affinities to thrombin. It could be suggested that there are some events during complex formation that have a larger impact on the affinity than the states of initial and final macromolecules. Possible mechanisms of the complex formation and a role of the duplex module in the association process are discussed.
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- 2019
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13. PeptoGrid—Rescoring Function for AutoDock Vina to Identify New Bioactive Molecules from Short Peptide Libraries
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Arthur O. Zalevsky, Alexander S. Zlobin, Vasilina R. Gedzun, Roman V. Reshetnikov, Maxim L. Lovat, Anton V. Malyshev, Igor I. Doronin, Gennady A. Babkin, and Andrey V. Golovin
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docking ,peptides ,rescoring ,gabab receptor ,Danio rerio ,Organic chemistry ,QD241-441 - Abstract
Peptides are promising drug candidates due to high specificity and standout safety. Identification of bioactive peptides de novo using molecular docking is a widely used approach. However, current scoring functions are poorly optimized for peptide ligands. In this work, we present a novel algorithm PeptoGrid that rescores poses predicted by AutoDock Vina according to frequency information of ligand atoms with particular properties appearing at different positions in the target protein’s ligand binding site. We explored the relevance of PeptoGrid ranking with a virtual screening of peptide libraries using angiotensin-converting enzyme and GABAB receptor as targets. A reasonable agreement between the computational and experimental data suggests that PeptoGrid is suitable for discovering functional leads.
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- 2019
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14. RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning.
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Stephen K. Burley, Charmi Bhikadiya, Chunxiao Bi, Sebastian Bittrich, Henry Chao, Li Chen 0022, Paul A. Craig, Gregg V. Crichlow, Kenneth Dalenberg, Jose M. Duarte, Shuchismita Dutta, Maryam Fayazi, Zukang Feng, Justin W. Flatt, Sai Ganesan, Sutapa Ghosh, David S. Goodsell, Rachel Kramer Green, Vladimir Guranovic, Jeremy Henry, Brian P. Hudson, Igor Khokhriakov, Catherine L. Lawson, Yuhe Liang, Robert Lowe, Ezra Peisach, Irina Persikova, Dennis W. Piehl, Yana Rose, Andrej Sali, Joan Segura, Monica Sekharan, Chenghua Shao, Brinda Vallat, Maria Voigt, Ben M. Webb, John D. Westbrook, Shamara Whetstone, Jasmine Young, Arthur O. Zalevsky, and Christine Zardecki
- Published
- 2023
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15. New QM/MM Implementation of the MOPAC2012 in the GROMACS.
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Arthur O. Zalevsky, Roman V. Reshetnikov, and Andrey V. Golovin
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- 2018
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16. New Binding Mode of SLURP Protein to a7 Nicotinic Acetylcholine Receptor Revealed by Computer Simulations.
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Igor D. Diankin, Denis S. Kudryavtsev, Arthur O. Zalevsky, Victor I. Tsetlin, and Andrey V. Golovin
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- 2018
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17. Modulation of Toll-like receptor 1 intracellular domain structure and activity by Zn2+ ions
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Daniil Vakhrameev, Xiaohui Wang, Irina A. Talyzina, Arthur O. Zalevsky, Sergey A. Goncharuk, Mikhail B. Shevtsov, Konstantin S. Mineev, Valentin Borshchevskiy, Vladislav A. Lushpa, Alexander S. Arseniev, Marina V. Goncharuk, Aleksandra Luginina, and Cong Lin
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QH301-705.5 ,In silico ,Medicine (miscellaneous) ,medicine.disease_cause ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Article ,Protein Domains ,ddc:570 ,parasitic diseases ,Extracellular ,medicine ,Humans ,Biology (General) ,Receptor ,X-ray crystallography ,Ions ,Toll-like receptor ,Mutation ,Chemistry ,biochemical phenomena, metabolism, and nutrition ,Toll-Like Receptor 1 ,Toll-Like Receptor 2 ,Toll-like receptors ,Zinc ,HEK293 Cells ,Cytoplasm ,Biophysics ,Molecular modelling ,General Agricultural and Biological Sciences ,Solution-state NMR ,Intracellular ,Cysteine - Abstract
Toll-like receptors (TLRs) play an important role in the innate immune response. While a lot is known about the structures of their extracellular parts, many questions are still left unanswered, when the structural basis of TLR activation is analyzed for the TLR intracellular domains. Here we report the structure and dynamics of TLR1 toll-interleukin like (TIR) cytoplasmic domain in crystal and in solution. We found that the TLR1-TIR domain is capable of specific binding of Zn with nanomolar affinity. Interactions with Zn are mediated by cysteine residues 667 and 686 and C667 is essential for the Zn binding. Potential structures of the TLR1-TIR/Zn complex were predicted in silico. Using the functional assays for the heterodimeric TLR1/2 receptor, we found that both Zn addition and Zn depletion affect the activity of TLR1, and C667A mutation disrupts the receptor activity. Analysis of C667 position in the TLR1 structure and possible effects of C667A mutation, suggests that zinc-binding ability of TLR1-TIR domain is critical for the receptor activation., Lushpa et al report the structure and dynamics of the TLR1 toll-interleukin like (TIR) cytoplasmic domain in both crystal and solution. They demonstrate that the TLR1 TIR domain is capable of specific binding of Zn with nanomolar affinity, which appears to be critical for receptor activation, and provide potential structures TLR1-TIR/Zn complex based on in silico data.
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- 2021
18. Disulfide Dimerization of Neuronal Calcium Sensor-1: Implications for Zinc and Redox Signaling
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Zernii, Viktoriia E. Baksheeva, Alexey V. Baldin, Arthur O. Zalevsky, Aliya A. Nazipova, Alexey S. Kazakov, Vasiliy I. Vladimirov, Neonila V. Gorokhovets, François Devred, Pavel P. Philippov, Alexandr V. Bazhin, Andrey V. Golovin, Andrey A. Zamyatnin, Dmitry V. Zinchenko, Philipp O. Tsvetkov, Sergei E. Permyakov, and Evgeni Yu.
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EF-hand ,NCS family ,neuronal calcium sensor-1 ,disulfide dimerization ,GRK1 ,zinc ,protein aggregation ,apoptosis ,neurodegeneration ,cancer - Abstract
Neuronal calcium sensor-1 (NCS-1) is a four-EF-hand ubiquitous signaling protein modulating neuronal function and survival, which participates in neurodegeneration and carcinogenesis. NCS-1 recognizes specific sites on cellular membranes and regulates numerous targets, including G-protein coupled receptors and their kinases (GRKs). Here, with the use of cellular models and various biophysical and computational techniques, we demonstrate that NCS-1 is a redox-sensitive protein, which responds to oxidizing conditions by the formation of disulfide dimer (dNCS-1), involving its single, highly conservative cysteine C38. The dimer content is unaffected by the elevation of intracellular calcium levels but increases to 10–30% at high free zinc concentrations (characteristic of oxidative stress), which is accompanied by accumulation of the protein in punctual clusters in the perinuclear area. The formation of dNCS-1 represents a specific Zn2+-promoted process, requiring proper folding of the protein and occurring at redox potential values approaching apoptotic levels. The dimer binds Ca2+ only in one EF-hand per monomer, thereby representing a unique state, with decreased α-helicity and thermal stability, increased surface hydrophobicity, and markedly improved inhibitory activity against GRK1 due to 20-fold higher affinity towards the enzyme. Furthermore, dNCS-1 can coordinate zinc and, according to molecular modeling, has an asymmetrical structure and increased conformational flexibility of the subunits, which may underlie their enhanced target-binding properties. In HEK293 cells, dNCS-1 can be reduced by the thioredoxin system, otherwise accumulating as protein aggregates, which are degraded by the proteasome. Interestingly, NCS-1 silencing diminishes the susceptibility of Y79 cancer cells to oxidative stress-induced apoptosis, suggesting that NCS-1 may mediate redox-regulated pathways governing cell death/survival in response to oxidative conditions.
- Published
- 2021
- Full Text
- View/download PDF
19. Mechanism of Zn
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Viktoriia E, Baksheeva, Andrei Yu, Roman, Claude, Villard, François, Devred, Deborah, Byrne, Dahbia, Yatoui, Arthur O, Zalevsky, Alisa A, Vologzhannikova, Andrey S, Sokolov, Sergei E, Permyakov, Andrey V, Golovin, Gary S, Shaw, Philipp O, Tsvetkov, and Evgeni Yu, Zernii
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inorganic chemicals ,Models, Molecular ,Binding Sites ,calcium ,Protein Conformation ,S100 Proteins ,zinc ,ESI-MS ,ITC ,Article ,S100A1 ,Humans ,nanoDSF ,Protein Binding ,Signal Transduction - Abstract
S100A1 is a member of the S100 family of small ubiquitous Ca2+-binding proteins, which participates in the regulation of cell differentiation, motility, and survival. It exists as homo- or heterodimers. S100A1 has also been shown to bind Zn2+, but the molecular mechanisms of this binding are not yet known. In this work, using ESI-MS and ITC, we demonstrate that S100A1 can coordinate 4 zinc ions per monomer, with two high affinity (KD~4 and 770 nm) and two low affinity sites. Using competitive binding experiments between Ca2+ and Zn2+ and QM/MM molecular modeling we conclude that Zn2+ high affinity sites are located in the EF-hand motifs of S100A1. In addition, two lower affinity sites can bind Zn2+ even when the EF-hands are saturated by Ca2+, resulting in a 2Ca2+:S100A1:2Zn2+ conformer. Finally, we show that, in contrast to calcium, an excess of Zn2+ produces a destabilizing effect on S100A1 structure and leads to its aggregation. We also determined a higher affinity to Ca2+ (KD~0.16 and 24 μm) than was previously reported for S100A1, which would allow this protein to function as a Ca2+/Zn2+-sensor both inside and outside cells, participating in diverse signaling pathways under normal and pathological conditions.
- Published
- 2021
20. Molecular coevolution of nuclear and nucleolar localization signals inside basic domain of HIV-1 Tat
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Gleb Bourenkov, Daria M. Potashnikova, Arthur O. Zalevsky, Olga M. Lisitsyna, Margarita A. Kurnaeva, Anastasia I. Kachalova, Andrey V. Golovin, Eugene V. Sheval, Anna V. Tvorogova, Yana R. Musinova, Maria Y. Shubina, Maria A Tikhomirova, Eugene A. Arifulin, Yegor S. Vassetzky, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques (METSY), and Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
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Signal peptide ,Gene Expression Regulation, Viral ,Models, Molecular ,Nucleolus ,[SDV]Life Sciences [q-bio] ,Immunology ,Nuclear Localization Signals ,HIV Infections ,Biology ,Microbiology ,Evolution, Molecular ,Transactivation ,03 medical and health sciences ,Structure-Activity Relationship ,Viral Proteins ,Transcription (biology) ,Virology ,Consensus Sequence ,medicine ,NLS ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Peptide sequence ,030304 developmental biology ,chemistry.chemical_classification ,Cell Nucleus ,0303 health sciences ,Binding Sites ,030302 biochemistry & molecular biology ,Amino acid ,Cell biology ,Virus-Cell Interactions ,Cell nucleus ,Protein Transport ,medicine.anatomical_structure ,chemistry ,Insect Science ,Viral evolution ,Host-Pathogen Interactions ,HIV-1 ,tat Gene Products, Human Immunodeficiency Virus ,Function (biology) ,Nuclear localization sequence ,Cell Nucleolus ,Protein Binding - Abstract
During evolution, viruses had to adapt to an increasingly complex environment of eukaryotic cells. Viral proteins that need to enter the cell nucleus or associate with nucleoli possess nuclear localization signals (NLSs) and nucleolar localization signals (NoLSs) for nuclear and nucleolar accumulation, respectively. As viral proteins are relatively small, acquisition of novel sequences seems to be a more complicated task for viruses than for eukaryotes. Here, we carried out a comprehensive analysis of the basic domain (BD) of HIV-1 Tat to show how viral proteins might evolve with NLSs and NoLSs without an increase in protein size. The HIV-1 Tat BD is involved in several functions, the most important being the transactivation of viral transcription. The BD also functions as an NLS, although it is substantially longer than a typical NLS. It seems that different regions in the BD could function as NLSs due to its enrichment with positively charged amino acids. Additionally, the high positive net charge inevitably causes the BD to function as an NoLS through a charge-specific mechanism. The integration of NLSs and NoLSs into functional domains enriched with positively charged amino acids might be a mechanism that allows the condensation of different functional sequences in small protein regions and, as a result, reduces protein size, influencing the origin and evolution of NLSs and NoLSs in viruses. IMPORTANCE Here, we investigated the molecular mechanism of nuclear localization signal (NLS) and nucleolar localization signal (NoLS) integration into the basic domain of HIV-1 Tat ((49)RKKRRQRRR(57)) and found that these two supplementary functions (i.e., function of NLS and function of NoLS) are embedded in the basic domain amino acid sequence. The integration of NLSs and NoLSs into functional domains of viral proteins enriched with positively charged amino acids is a mechanism that allows the concentration of different functions within small protein regions. Integration of NLS and NoLS into functional protein domains might have influenced the viral evolution, as this could prevent an increase in the protein size.
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- 2021
21. The Preferable Binding Pose of Canonical Butyrylcholinesterase Substrates Is Unproductive for Echothiophate
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Arthur O. Zalevsky, Andrey V. Golovin, Yu. A. Mokrushina, Olga V. Kartseva, Alexander Zlobin, and Ivan V. Smirnov
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0301 basic medicine ,Molecular model ,biology ,Echothiophate ,Metadynamics ,Active site ,Biochemistry ,Combinatorial chemistry ,Butyrylthiocholine ,QM/MM ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,biology.protein ,medicine ,Molecular Medicine ,Butyrylcholine ,Molecular Biology ,Butyrylcholinesterase ,Biotechnology ,medicine.drug - Abstract
In this paper, we, for the first time, describe the interaction between the butyrylcholinesterase enzyme and echothiophate, a popular model compound and an analogue of the chemical warfare agents VX and VR, at the atomistic level. Competition between the two echothiophate conformations in the active site was found using molecular modeling techniques. The first one is close to the mode of binding of the substrates of choline series (butyrylcholine and butyrylthiocholine) and is inhibitory, since it is unable to react with the enzyme. The second one is characterized by a significantly worse estimated binding affinity and is reactive. Thus, echothiophate combines the features of two types of inhibitors: competitive and suicidal. This observation will help clarify the kinetic reaction scheme in order to accurately assess the kinetic constants, which is especially important when designing new butyrylcholinesterase variants capable of full-cycle hydrolysis of organophosphorus compounds.
- Published
- 2018
22. A structural biology community assessment of AlphaFold 2 applications
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Pires Dev, Janet M. Thornton, Kundrotas P, Roman A. Laskowski, Jänes J, Tristan I. Croll, Rodrigues Chm, Mehmet Akdel, Sameer Velankar, Bryant P, Alistair Dunham, Durairaj J, Amelie Stein, Wensi Zhu, David F. Burke, Gabriele Pozzati, Norman E. Davey, Arthur O. Zalevsky, Alfonso Valencia, Porta Pardo E, Shenoy A, Liam Good, Sergey Ovchinnikov, Arne Elofsson, Kresten Lindorff-Larsen, Ruiz Serra, Pedro Beltrao, Bálint Mészáros, Adam Frost, David B. Ascher, and Neera Borkakoti
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Science research ,Protein structure ,Structural biology ,Computer science ,Protein Data Bank (RCSB PDB) ,Computational biology - Abstract
Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods have led to protein structure predictions that have reached the accuracy of experimentally determined models. While this has been independently verified, the implementation of these methods across structural biology applications remains to be tested. Here, we evaluate the use of AlphaFold 2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modelling of interactions; and modelling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modelled when compared to homology modelling, identifying structural features rarely seen in the PDB. AF2-based predictions of protein disorder and protein complexes surpass state-of-the-art tools and AF2 models can be used across diverse applications equally well compared to experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life science research.
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- 2021
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23. Genomic signatures of recombination in a natural population of the bdelloid rotifer Adineta vaga
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Evgeny S. Gerasimov, Irina A. Yushenova, Aleksey A. Penin, Sergey Naumenko, Yan R. Galimov, Svetlana G. Ozerova, Arthur O. Zalevsky, Georgii A. Bazykin, E. Mnatsakanova, Irina R. Arkhipova, Alexey S. Kondrashov, Fernando Santos Rodríguez, Maria D. Logacheva, Olga A. Vakhrusheva, and Tatiana V. Neretina
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0106 biological sciences ,0301 basic medicine ,Linkage disequilibrium ,Science ,Population ,Rotifera ,General Physics and Astronomy ,Evolutionary biology ,Biology ,010603 evolutionary biology ,01 natural sciences ,Article ,Evolutionary genetics ,Linkage Disequilibrium ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Molecular evolution ,Phylogenetics ,Genetic variation ,Genetics ,Animals ,education ,Alleles ,Phylogeny ,Recombination, Genetic ,education.field_of_study ,Genome ,Multidisciplinary ,Whole Genome Sequencing ,Human evolutionary genetics ,General Chemistry ,Sexual reproduction ,Genetics, Population ,Germ Cells ,030104 developmental biology ,Haplotypes ,Natural population growth - Abstract
Sexual reproduction is almost ubiquitous among extant eukaryotes. As most asexual lineages are short-lived, abandoning sex is commonly regarded as an evolutionary dead end. Still, putative anciently asexual lineages challenge this view. One of the most striking examples are bdelloid rotifers, microscopic freshwater invertebrates believed to have completely abandoned sexual reproduction tens of Myr ago. Here, we compare whole genomes of 11 wild-caught individuals of the bdelloid rotifer Adineta vaga and present evidence that some patterns in its genetic variation are incompatible with strict clonality and lack of genetic exchange. These patterns include genotype proportions close to Hardy-Weinberg expectations within loci, lack of linkage disequilibrium between distant loci, incongruent haplotype phylogenies across the genome, and evidence for hybridization between divergent lineages. Analysis of triallelic sites independently corroborates these findings. Our results provide evidence for interindividual genetic exchange and recombination in A. vaga, a species previously thought to be anciently asexual., Ancient, asexual lineages are rare as a lack of recombination is usually an evolutionary dead end. Here, authors compare complete genomes of 11 individual bdelloid rotifers that suggest evidence of regular genetic exchange between individuals in a species that was previously thought to be asexual.
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- 2020
24. Zinc Binds to RRM2 Peptide of TDP-43
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Françoise Guerlesquin, Rémy Puppo, Andrei Yu. Roman, Arthur O. Zalevsky, Régine Lebrun, Dahbia Yatoui, François Devred, Andrey V. Golovin, Philipp O. Tsvetkov, Lomonosov Moscow State University (MSU), Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Microbiologie de la Méditerranée (IMM), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Devred, François, National Research University Higher School of Economics [Moscow] (HSE), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
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0301 basic medicine ,Models, Molecular ,Heterogeneous nuclear ribonucleoprotein ,Magnetic Resonance Spectroscopy ,Protein Conformation ,TDP-43 ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,RNA-binding protein ,Peptide ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,QM/MM ,Catalysis ,Article ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Protein Domains ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Transcription (biology) ,Computer Simulation ,Amino Acid Sequence ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,zinc ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,RNA ,Isothermal titration calorimetry ,General Medicine ,3. Good health ,Computer Science Applications ,DNA-Binding Proteins ,[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,RNA splicing ,Biophysics ,Peptides ,030217 neurology & neurosurgery ,DNA ,Protein Binding - Abstract
Transactive response DNA and RNA binding protein 43 kDa (TDP-43) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP), which is involved in several steps of protein production including transcription and splicing. Its aggregates are frequently observed in motor neurons from amyotrophic lateral sclerosis patients and in the most common variant of frontotemporal lobar degeneration. Recently it was shown that TDP-43 is able to bind Zn2+ by its RRM domain. In this work, we have investigated Zn2+ binding to a short peptide 256&ndash, 264 from C-terminus of RRM2 domain using isothermal titration calorimetry, electrospray ionization mass spectrometry, QM/MM simulations, and NMR spectroscopy. We have found that this peptide is able to bind zinc ions with a Ka equal to 1.6 ×, 105 M&minus, 1. Our findings suggest the existence of a zinc binding site in the C-terminal region of RRM2 domain. Together with the existing structure of the RRM2 domain of TDP-43 we propose a model of its complex with Zn2+ which illustrates how zinc might regulate DNA/RNA binding.
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- 2020
25. A Fluorescent Assay to Search for Inhibitors of HIV-1 Integrase Interactions with Human Ku70 Protein, and Its Application for Characterization of Oligonucleotide Inhibitors
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Andrey Anisenko, Simon Galkin, Arthur O. Zalevsky, Anna Rozina, and Marina Gottikh
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Models, Molecular ,0301 basic medicine ,Molecular model ,High-throughput screening ,lcsh:QR1-502 ,Phosphorothioate Oligonucleotides ,HIV Integrase ,Microbial Sensitivity Tests ,Virus Replication ,Biochemistry ,high-throughput screening ,Article ,lcsh:Microbiology ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,oligonucleotide inhibitors ,HIV-1 integrase ,Humans ,Protein Interaction Domains and Motifs ,Ku70 ,HIV Integrase Inhibitors ,Ku Autoantigen ,Molecular Biology ,Fluorescent Dyes ,biology ,Oligonucleotide ,Chemistry ,fluorescence assay ,Recombinant Proteins ,High-Throughput Screening Assays ,Integrase ,Molecular Docking Simulation ,030104 developmental biology ,Viral replication ,030220 oncology & carcinogenesis ,protein-protein interaction inhibitors ,fluorescent tags ,HIV-1 ,Nucleic acid ,biology.protein ,Eosine Yellowish-(YS) ,Conjugate - Abstract
The search for compounds that can inhibit the interaction of certain viral proteins with their cellular partners is a promising trend in the development of antiviral drugs. We have previously shown that binding of HIV-1 integrase with human Ku70 protein is essential for viral replication. Here, we present a novel, cheap, and fast assay to search for inhibitors of these proteins&rsquo, binding based on the usage of genetically encoded fluorescent tags linked to both integrase and Ku70. Using this approach, we have elucidated structure-activity relationships for a set of oligonucleotide conjugates with eosin and shown that their inhibitory activity is primarily achieved through interactions between the conjugate nucleic bases and integrase. Molecular modeling of HIV-1 integrase in complex with the conjugates suggests that they can shield E212/L213 residues in integrase, which are crucial for its efficient binding to Ku70, in a length-dependent manner. Using the developed system, we have found the 11-mer phosphorothioate bearing 3&rsquo, end eosin-Y to be the most efficient inhibitor among the tested conjugates.
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- 2020
26. Alterations in proteome of human sclera associated with primary open-angle glaucoma involve proteins participating in regulation of the extracellular matrix
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Elena N, Iomdina, Natalya K, Tikhomirova, Alexander M, Bessmertny, Marina V, Serebryakova, Viktoriia E, Baksheeva, Arthur O, Zalevsky, Vladislav I, Kotelin, Olga A, Kiseleva, Sbrui M, Kosakyan, Andrey A, Zamyatnin, Pavel P, Philippov, and Evgeni Yu, Zernii
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Adult ,Male ,Proteomics ,genetic structures ,Proteome ,Cartilage Oligomeric Matrix Protein ,Extracellular Vesicles ,Tandem Mass Spectrometry ,Humans ,Vimentin ,Protein Interaction Maps ,Annexin A2 ,Serum Albumin ,Aged ,Aged, 80 and over ,Computational Biology ,Middle Aged ,eye diseases ,Extracellular Matrix ,Up-Regulation ,Serum Amyloid P-Component ,Angiopoietin-like Proteins ,Gene Ontology ,Female ,sense organs ,Glaucoma, Open-Angle ,Sclera ,Genome-Wide Association Study ,Research Article - Abstract
Purpose Primary open-angle glaucoma (POAG) is a common ocular disease, associated with abnormalities in aqueous humor circulation and an increase in intraocular pressure (IOP), leading to progressive optical neuropathy and loss of vision. POAG pathogenesis includes alterations of the structural properties of the sclera, especially in the optic nerve head area, contributing to the degeneration of the retinal ganglion cells. Abnormal sclera biomechanics hinder adequate compensation of IOP fluctuations, thus aggravating POAG progression. The proteomic basis of biomechanical disorders in glaucomatous sclera remains poorly understood. This study is aimed at revealing alterations in major scleral proteins, associated with POAG, at different stages of the disease and with different IOP conditions. Methods Samples of sclera were collected from 67 patients with POAG during non-penetrating deep sclerectomy and from nine individuals without POAG. Scleral proteins were extracted with a strong lysis buffer, containing a combination of an ionic detergent, a chaotropic agent, and a disulfide reducing agent, and were separated using sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). The major scleral proteins were selected, subjected to in-gel digestion, and identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF)/TOF mass spectrometry (MS), coupled with tandem mass spectrometry (MS/MS). The specific POAG-associated alterations of the selected proteins were analyzed with SDS–PAGE and confirmed with western blotting of the scleral extracts, using the respective antibodies. The group of POAG-associated proteins was analyzed using Gene Ontology and genome-wide association study enrichment and protein–protein interaction network prediction. Results A total of 11 proteins were identified, among which six proteins, namely, vimentin, angiopoietin-related protein 7, annexin A2, serum amyloid P component, serum albumin, and thrombospondin-4, were found to be upregulated in the sclera of patients with advanced and terminal POAG. In the early stages of the disease, thrombospondin-4 level was, on the contrary, reduced when compared with the control, whereas the concentration of vimentin varied, depending on the IOP level. Moreover, angiopoietin-related protein 7 manifested as two forms, exhibiting opposite behavior: The common 45 kDa form grew with the progression of POAG, whereas the 35 kDa (apparently non-glycosylated) form was absent in the control samples, appeared in patients with early POAG, and decreased in concentration over the course of the disease. Functional bioinformatics analysis linked the POAG-associated proteins with IOP alterations and predicted their secretion into extracellular space and their association with extracellular vesicles and a collagen-containing extracellular matrix. Conclusions POAG is accompanied by alterations of the scleral proteome, which represent a novel hallmark of the disease and can reflect pathological changes in scleral biochemistry and biomechanics. The potential mechanisms underlying these changes relate mainly to the structure of the extracellular matrix, protein glycosylation, and calcium binding, and may involve fibroblast cytoskeleton regulation, as well as oxidative and inflammatory responses.
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- 2020
27. Membrane Binding of Neuronal Calcium Sensor-1: Highly Specific Interaction with Phosphatidylinositol-3-Phosphate
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Arthur O. Zalevsky, Andrey A. Zamyatnin, Ekaterina L. Nemashkalova, Viktoriia E. Baksheeva, Natalia K. Tikhomirova, Alexander M. Firsov, Dmitry V. Zinchenko, Vasily I. Vladimirov, S.E. Permyakov, Yuri N. Antonenko, Evgeni Yu. Zernii, and Pavel P. Philippov
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0301 basic medicine ,Light ,lcsh:QR1-502 ,PI3P ,Ligands ,Hippocampus ,Myristic Acid ,Biochemistry ,lcsh:Microbiology ,neuronal calcium sensor-1 ,phosphatidylinositol-3-phosphate ,chemistry.chemical_compound ,0302 clinical medicine ,Phosphatidylinositol Phosphates ,myristoyl group ,Magnesium ,Neurons ,NCS-1 ,biology ,Temperature ,Phosphatidylserine ,phosphoinositides ,Molecular Docking Simulation ,Membrane ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Protein Binding ,Signal Transduction ,Neuronal Calcium-Sensor Proteins ,Static Electricity ,Phospholipid ,N-terminal myristoylation ,Article ,03 medical and health sciences ,Protein Domains ,Humans ,Phosphatidylinositol ,membrane binding ,Molecular Biology ,Myristoylation ,Binding Sites ,Lysine ,Phosphatidylinositol 3-phosphate ,Neuropeptides ,Hydrogen Bonding ,phospholipid-binding proteins ,Spectrometry, Fluorescence ,030104 developmental biology ,Neuronal calcium sensor-1 ,chemistry ,neuronal calcium sensors ,Liposomes ,Mutation ,Biophysics ,biology.protein ,Calcium ,030217 neurology & neurosurgery - Abstract
Neuronal calcium sensors are a family of N-terminally myristoylated membrane-binding proteins possessing a different intracellular localization and thereby targeting unique signaling partner(s). Apart from the myristoyl group, the membrane attachment of these proteins may be modulated by their N-terminal positively charged residues responsible for specific recognition of the membrane components. Here, we examined the interaction of neuronal calcium sensor-1 (NCS-1) with natural membranes of different lipid composition as well as individual phospholipids in form of multilamellar liposomes or immobilized monolayers and characterized the role of myristoyl group and N-terminal lysine residues in membrane binding and phospholipid preference of the protein. NCS-1 binds to photoreceptor and hippocampal membranes in a Ca2+-independent manner and the binding is attenuated in the absence of myristoyl group. Meanwhile, the interaction with photoreceptor membranes is less dependent on myristoylation and more sensitive to replacement of K3, K7, and/or K9 of NCS-1 by glutamic acid, reflecting affinity of the protein to negatively charged phospholipids. Consistently, among the major phospholipids, NCS-1 preferentially interacts with phosphatidylserine and phosphatidylinositol with micromolar affinity and the interaction with the former is inhibited upon mutating of N-terminal lysines of the protein. Remarkably, NCS-1 demonstrates pronounced specific binding to phosphoinositides with high preference for phosphatidylinositol-3-phosphate. The binding does not depend on myristoylation and, unexpectedly, is not sensitive to the charge inversion mutations. Instead, phosphatidylinositol-3-phosphate can be recognized by a specific site located in the N-terminal region of the protein. These data provide important novel insights into the general mechanism of membrane binding of NCS-1 and its targeting to specific phospholipids ensuring involvement of the protein in phosphoinositide-regulated signaling pathways.
- Published
- 2020
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28. Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers
- Author
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Alexey A. Belogurov, Spyros D. Chatziefthimiou, Richard A. Lerner, Ekaterina Round, Yuliana A. Mokrushina, T. V. Bobik, Alexander G. Gabibov, Anastasia V. Stepanova, Andrey V. Golovin, G. Michael Blackburn, Gleb Bourenkov, Matthias Wilmanns, Alexander Zlobin, O. G. Shamborant, Ivan V. Smirnov, Alexey Stepanov, Kirill A. Konovalov, Arthur O. Zalevsky, Stanislav S. Terekhov, Sofiya O. Pipiya, Jia Xie, and Alexander A. Makarov
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0301 basic medicine ,phosphoryl transfer ,Stereochemistry ,antibody bioscavengers ,01 natural sciences ,Molecular mechanics ,03 medical and health sciences ,Stereospecificity ,stereospecificity ,Nucleophile ,Reactivity (chemistry) ,designed biocatalysts ,Multidisciplinary ,QM/MM computation ,010405 organic chemistry ,Chemistry ,Metadynamics ,Biological Sciences ,Transition state ,0104 chemical sciences ,Biophysics and Computational Biology ,030104 developmental biology ,Covalent bond ,Stereoselectivity ,ddc:500 - Abstract
Proceedings of the National Academy of Sciences of the United States of America 117(37), 22841 - 22848 (2020). doi:10.1073/pnas.2010317117, Quantum mechanics/molecular mechanics (QM/MM) maturation of an immunoglobulin (Ig) powered by supercomputation delivers novel functionality to this catalytic template and facilitates artificial evolution of biocatalysts. We here employ density functional theory-based (DFT-b) tight binding and funnel metadynamics to advance our earlier QM/MM maturation of A17 Ig-paraoxonase (WTIgP) as a reactibody for organophosphorus toxins. It enables regulation of biocatalytic activity for tyrosine nucleophilic attack on phosphorus. The single amino acid substitution l-Leu47Lys results in 340-fold enhanced reactivity for paraoxon. The computed ground-state complex shows substrate-induced ionization of the nucleophilic l-Tyr37, now H-bonded to l-Lys47, resulting from repositioning of l-Lys47. Multiple antibody structural homologs, selected by phenylphosphonate covalent capture, show contrasting enantioselectivities for a P-chiral phenylphosphonate toxin. That is defined by crystallographic analysis of phenylphosphonylated reaction products for antibodies A5 and WTIgP. DFT-b analysis using QM regions based on these structures identifies transition states for the favored and disfavored reactions with surprising results. This stereoselection analysis is extended by funnel metadynamics to a range of WTIgP variants whose predicted stereoselectivity is endorsed by experimental analysis. The algorithms used here offer prospects for tailored design of highly evolved, genetically encoded organophosphorus scavengers and for broader functionalities of members of the Ig superfamily, including cell surface-exposed receptors., Published by National Acad. of Sciences, Washington, DC
- Published
- 2020
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29. NHEJ pathway is involved in post-integrational DNA repair due to Ku70 binding to HIV-1 integrase
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Timofei S. Zatsepin, Ekaterina Knyazhanskaya, Andrey Anisenko, Arthur O. Zalevsky, Olga Shadrina, Dmitriy Mazurov, Marina Gottikh, and Anastasia Kalinina
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Post integrational gap repair ,lcsh:Immunologic diseases. Allergy ,DNA End-Joining Repair ,Ku80 ,DNA repair ,Mutant ,HIV Integrase ,Integrase ,DNA-PK ,03 medical and health sciences ,chemistry.chemical_compound ,Virology ,Humans ,CRISPR ,DNA Breaks, Double-Stranded ,Ku70 ,Ku Autoantigen ,NHEJ ,030304 developmental biology ,0303 health sciences ,Host Microbial Interactions ,biology ,Cas9 ,Research ,030302 biochemistry & molecular biology ,Cell biology ,Infectious Diseases ,chemistry ,HIV-1 ,biology.protein ,lcsh:RC581-607 ,Metabolic Networks and Pathways ,DNA - Abstract
BackgroundHIV-1 integration results in genomic DNA gaps that are repaired by cellular DNA repair pathways. This step of the lentiviral life cycle remains poorly understood despite its crucial importance for successful replication. We and others reported that Ku70 protein of the non-homologous end joining pathway (NHEJ) directly binds HIV-1 integrase (IN). Here, we studied the importance of this interaction for post-integrational gap repair and the recruitment of NHEJ factors in this process.ResultsWe engineered HIV-based pseudovirus with mutant IN defective in Ku70 binding and generated heterozygous Ku70, Ku80 and DNA-PKcs human knockout (KO) cells using CRISPR/Cas9. KO of either of these proteins or inhibition of DNA-PKcs catalytic activity substantially decreased the infectivity of HIV-1 with native IN but not with the mutant one. We used a recently developed qPCR assay for the measurement of gap repair efficiency to show that HIV-1 with mutant IN was defective in DNA post-integrational repair, whereas the wild type virus displayed such a defect only when NHEJ system was disrupted in any way. This effect was present in CRISPR/Cas9 modified 293T cells, in Jurkat and CEM lymphoid lines and in primary human PBMCs.ConclusionsOur data provide evidence that IN recruits DNA-PK to the site of HIV-1 post-integrational repair due to Ku70 binding—a novel finding that explains the involvement of DNA-PK despite the absence of free double stranded DNA breaks. In addition, our data clearly indicate the importance of interactions between HIV-1 IN and Ku70 in HIV-1 replication at the post-integrational repair step.
- Published
- 2019
30. A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding
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Alexandra A. Kulikova, Ivan V. Smirnov, Alexey A. Belogurov, Hua Jane Lou, Arthur O. Zalevsky, Yuliana A. Mokrushina, Stanislav S. Terekhov, Andrey V. Golovin, Benjamin E. Turk, Anton S. Nazarov, Gleb Bourenkov, Alexander Zlobin, Matthias Wilmanns, Alexander G. Gabibov, Ilya A. Osterman, Sidney Altman, and Vladimir A. Mitkevich
- Subjects
0303 health sciences ,Multidisciplinary ,Subfamily ,biology ,medicine.drug_class ,Kinase ,Chemistry ,030302 biochemistry & molecular biology ,Antibiotics ,Substrate (chemistry) ,Active site ,SciAdv r-articles ,Phosphotransferase ,03 medical and health sciences ,Antibiotic resistance ,Biochemistry ,Structural Biology ,medicine ,biology.protein ,Phosphorylation ,ddc:500 ,Research Articles ,030304 developmental biology ,Research Article - Abstract
Science advances 6(26), eaaz9861 - (2020). doi:10.1126/sciadv.aaz9861, Microbial communities are self-controlled by repertoires of lethal agents, the antibiotics. In their turn, these antibiotics are regulated by bioscavengers that are selected in the course of evolution. Kinase-mediated phosphorylation represents one of the general strategies for the emergence of antibiotic resistance. A new subfamily of AmiN-like kinases, isolated from the Siberian bear microbiome, inactivates antibiotic amicoumacin by phosphorylation. The nanomolar substrate affinity defines AmiN as a phosphotransferase with a unique catalytic efficiency proximal to the diffusion limit. Crystallographic analysis and multiscale simulations revealed a catalytically perfect mechanism providing phosphorylation exclusively in the case of a closed active site that counteracts substrate promiscuity. AmiN kinase is a member of the previously unknown subfamily representing the first evidence of a specialized phosphotransferase bioscavenger., Published by Assoc., Washington, DC [u.a.]
- Published
- 2019
31. A coarse-grained model for DNA origami
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Arthur O. Zalevsky, Andrey V. Golovin, Roman V. Reshetnikov, Anastasia V Stolyarova, Galina Pavlova, Dmitry V. Klinov, Anna D. Protopopova, and Dmitry Y. Panteleev
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0301 basic medicine ,Base pair ,Molecular Dynamics Simulation ,Biology ,Microscopy, Atomic Force ,Energy minimization ,01 natural sciences ,03 medical and health sciences ,Molecular dynamics ,0103 physical sciences ,Microscopy ,Genetics ,Humans ,DNA origami ,Glial Cell Line-Derived Neurotrophic Factor ,Spectroscopy ,Base Pairing ,Quantitative Biology::Biomolecules ,Base Sequence ,010304 chemical physics ,Atomic force microscopy ,Cryoelectron Microscopy ,Computational Biology ,DNA ,030104 developmental biology ,Förster resonance energy transfer ,Nucleic Acid Conformation ,Biological system - Abstract
Modeling tools provide a valuable support for DNA origami design. However, current solutions have limited application for conformational analysis of the designs. In this work we present a tool for a thorough study of DNA origami structure and dynamics. The tool is based on a novel coarse-grained model dedicated to geometry optimization and conformational analysis of DNA origami. We explored the ability of the model to predict dynamic behavior, global shapes, and fine details of two single-layer systems designed in hexagonal and square lattices using atomic force microscopy, Förster resonance energy transfer spectroscopy, and all-atom molecular dynamic simulations for validation of the results. We also examined the performance of the model for multilayer systems by simulation of DNA origami with published cryo-electron microscopy and atomic force microscopy structures. A good agreement between the simulated and experimental data makes the model suitable for conformational analysis of DNA origami objects. The tool is available at http://vsb.fbb.msu.ru/cosm as a web-service and as a standalone version.
- Published
- 2017
32. Putative Mechanisms Underlying High Inhibitory Activities of Bimodular DNA Aptamers to Thrombin
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Alexander M. Arutyunyan, V. Legatova, Elena Zavyalova, Vadim N. Tashlitsky, Rugiya Sh Alieva, Alexey Kopylov, and Arthur O. Zalevsky
- Subjects
Serine Proteinase Inhibitors ,structure–activity relationship ,Aptamer ,Oligonucleotides ,lcsh:QR1-502 ,G-quadruplex ,Biochemistry ,Article ,lcsh:Microbiology ,03 medical and health sciences ,thermodynamics ,0302 clinical medicine ,Thrombin ,medicine ,Structure–activity relationship ,Molecular Biology ,Protein Unfolding ,030304 developmental biology ,0303 health sciences ,Chemistry ,Oligonucleotide ,Aptamers, Nucleotide ,DNA aptamer ,thrombin ,conformational polymorphism ,Duplex (building) ,Nucleic acid ,Biophysics ,030217 neurology & neurosurgery ,medicine.drug ,Macromolecule - Abstract
Nucleic acid aptamers are prospective molecular recognizing elements. Similar to antibodies, aptamers are capable of providing specific recognition due to their spatial structure. However, the apparent simplicity of oligonucleotide folding is often elusive, as there is a balance between several conformations and, in some cases, oligomeric structures. This research is focused on establishing a thermodynamic background and the conformational heterogeneity of aptamers taking a series of thrombin DNA aptamers having G-quadruplex and duplex modules as an example. A series of aptamers with similar modular structures was characterized with spectroscopic and chromatographic techniques, providing examples of the conformational homogeneity of aptamers with high inhibitory activity, as well as a mixture of monomeric and oligomeric species for aptamers with low inhibitory activity. Thermodynamic parameters for aptamer unfolding were calculated, and their correlation with aptamer functional activity was found. Detailed analysis of thrombin complexes with G-quadruplex aptamers bound to exosite I revealed the similarity of the interfaces of aptamers with drastically different affinities to thrombin. It could be suggested that there are some events during complex formation that have a larger impact on the affinity than the states of initial and final macromolecules. Possible mechanisms of the complex formation and a role of the duplex module in the association process are discussed.
- Published
- 2019
33. New QM/MM Implementation of the MOPAC2012 in the GROMACS
- Author
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Andrey V. Golovin, Roman V. Reshetnikov, and Arthur O. Zalevsky
- Subjects
Set (abstract data type) ,QM/MM ,Computer science ,Ab initio ,Rational design ,Catalytic antibody ,Biochemical engineering - Abstract
Hybrid QM/MM simulations augmented with enhanced sampling techniques proved to be advantageous in different usage scenarios, from studies of biological systems to drug and enzyme design. However, there are several factors that limit the applicability of the approach. First, typical biologically relevant systems are too large and hence computationally expensive for many QM methods. Second, a majority of fast non ab initio QM methods contain parameters for a very limited set of elements, which restrains their usage for applications involving radionuclides and other unusual compounds. Therefore, there is an incessant need for new tools which will expand both type and size of simulated objects. Here we present a novel combination of widely accepted molecular modelling packages GROMACS and MOPAC2012 and demonstrate its applicability for design of a catalytic antibody capable of organophosphorus compound hydrolysis.
- Published
- 2018
34. Recombination in a natural population of the bdelloid rotiferAdineta vaga
- Author
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Aleksey A. Penin, Maria D. Logacheva, E. Mnatsakanova, Alexey S. Kondrashov, Evgeny S. Gerasimov, Yan R. Galimov, Irina A. Yushenova, Georgii A. Bazykin, Tatiana V. Neretina, Svetlana G. Ozerova, Arthur O. Zalevsky, Irina R. Arkhipova, and Olga A. Vakhrusheva
- Subjects
Linkage disequilibrium ,education.field_of_study ,Natural selection ,Meiosis ,Evolutionary biology ,Population ,Genetic structure ,Asexual reproduction ,Timema ,Biology ,education ,biology.organism_classification ,Sexual reproduction - Abstract
Sexual reproduction which involves alternation of meiosis and syngamy is the ancestral condition of extant eukaryotes. Transitions to asexual reproduction were numerous, but most of the resulting eukaryotic lineages are rather short-lived. Still, there are several exceptions to this rule including darwinulid ostracods1,2and timema stick insects3. The most striking of them is bdelloid rotifers4–6, microscopic freshwater invertebrates which underwent an extensive adaptive radiation after apparently losing meiosis over 10 Mya. Indeed, both the lack of males in numerous bdelloid species and the lack of proper homology between chromosomes6rule out ordinary sex. However, this does not exclude the possibility of some other mode of interindividual genetic exchange and recombination in their populations7. Recent analyses based on a few loci suggested genetic exchanges in this group8,9, although this has been controversial10. Here, we compare complete genomes of 11 individuals from the wild population of the bdelloid rotiferAdineta vaga,and show that its genetic structure, which involves Hardy-Weinberg proportions of genotypes within loci and lack of linkage disequilibrium between distant loci, is incompatible with strictly clonal reproduction. Instead, it can emerge only under ongoing recombination between different individuals within this species, possibly through transformation. Such a genetic structure makes the population immune to negative long-term consequences of the loss of conventional meiosis11, although this does not necessarily imply that interindividual genetic exchanges inA. vagaare directly maintained by natural selection.
- Published
- 2018
35. QM/MM Description of Newly Selected Catalytic Bioscavengers Against Organophosphorus Compounds Revealed Reactivation Stimulus Mediated by Histidine Residue in the Acyl-Binding Loop
- Author
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Tatiana Bobik, Yuliana A. Mokrushina, Alexander G. Gabibov, Alexey A. Belogurov, A. V. Stepanova, Andrey V. Golovin, Maria Aliseychik, Olga V. Kartseva, S. S. Terekhov, Arthur O. Zalevsky, Ivan V. Smirnov, Alexander Zlobin, and S. S. Panteleev
- Subjects
computer design ,0301 basic medicine ,bioscavenger ,Stereochemistry ,01 natural sciences ,Active center ,QM/MM ,03 medical and health sciences ,Acyl binding ,0103 physical sciences ,Catalytic triad ,Organophosphorus compound ,medicine ,Pharmacology (medical) ,Histidine ,Original Research ,Pharmacology ,chemistry.chemical_classification ,010304 chemical physics ,Paraoxon ,Chemistry ,lcsh:RM1-950 ,organophosphorus compound ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Catalytic cycle ,paraoxon ,butyrylcholinesterase ,ultrahigh-throughput screening ,medicine.drug - Abstract
Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its pKa, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme’s active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons.
- Published
- 2018
36. Technological prospects of developing DNA-modified biosensors based on carbon nanotubes
- Author
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R. D. Aydarkhanov, Andrey V. Golovin, I. A. Komarov, Arthur O. Zalevsky, and Ivan I. Bobrinetskiy
- Subjects
Aptamer ,Biophysics ,Nanotechnology ,Personal health monitoring ,Carbon nanotube ,DNA Aptamers ,law.invention ,chemistry.chemical_compound ,symbols.namesake ,Thrombin ,chemistry ,law ,medicine ,symbols ,Raman spectroscopy ,Biosensor ,DNA ,medicine.drug - Abstract
In this study, we investigated the response of DNA-modified carbon nanotubes in the presence of thrombin and albumin. Interactions between DNA aptamers and carbon nanotubes were analyzed by Raman spectroscopy and by measuring the resistance of the construct after each step of biosensor assembly. It was shown that aptamer binding to carbon nanotubes decreased the G-band intensity and lowered the resistance of the sensor structure. The responses of the sensor exposed to thrombin and albumin differed substantially from each other, which provides a basis for the development of a highly selective biosensor. These results can be used in the development of a new generation of personal health monitoring systems.
- Published
- 2015
37. A new species of Cyanea jellyfish sympatric to C. capillata in the White Sea
- Author
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Anna S. Lapashina, Margarita A. Ezhova, O. P. Konovalova, Ksenia N. Kosobokova, Philipp O. Gusev, Arthur O. Zalevsky, Nikita Kotlov, Anna A. Zheludkevich, Georgii A. Bazykin, Tatyana V. Neretina, Dmitry Medvedev, Azamat Gafurov, Ekaterina O. Nuzhdina, Natalia O. Lanina, Katerina S. Nosikova, and Glafira D. Kolbasova
- Subjects
Genetic divergence ,biology ,Genetic distance ,Sympatric speciation ,Ecology ,Biodiversity ,Zoology ,Taxonomy (biology) ,Scyphozoa ,Cyanea (jellyfish) ,General Agricultural and Biological Sciences ,Rhopalium ,biology.organism_classification - Abstract
Cyanea is a genus of large bloom-forming scyphozoans, including some of the most conspicuous rep- resentatives of megaplankton. Its taxonomy has been revised repeatedly throughout the last century due to the fact that most of the morphological characteristics ofCyanea species, such as color, structure of gastrovascular system and number of tentacles, may overlap greatly in different populations. Here, we report a new species ofCyanea,Cyaneatzetlinii sp. nov., from the White Sea, which is distinguishable from all previously describedCyanea species by an eye-spot-bearing bulb formed at the base of each rhopalium. This well-rec- ognizable morphological characteristic is supported at the molecular level by a substantial genetic distance in mito- chondrial (CO1: 9.6-10.6 %, 16S RNA: 3.1-3.5 %) as well as nuclear (ITS: 5.0 %, 18S RNA: 0.1 %) loci, making it the sister species to Cyanea capillata. Taking into account the young geological age of the White Sea and a substantial genetic divergence between C. tzetlinii sp. nov. and the nearest sister species, we suppose thatC.tzetlinii sp. nov. has been advected to the White Sea from elsewhere and may also inhabit other Arctic seas. Past ecological studies in the White Sea and possibly in other Arctic Seas could have conflatedC. tzetlinii sp. nov. with other species, which likely affected the analyses.
- Published
- 2015
38. Raman spectroscopy of disulfide bridges in thrombin
- Author
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A. Yu. Chikishev, V.N. Kruzhilin, Nikolai N. Brandt, Arthur O. Zalevsky, and Andrey V. Golovin
- Subjects
Crystallography ,symbols.namesake ,chemistry.chemical_compound ,Thrombin ,Chemistry ,medicine ,symbols ,Disulfide bond ,A protein ,Radiology, Nuclear Medicine and imaging ,Raman spectroscopy ,Dithiothreitol ,medicine.drug - Abstract
Disulfide bridges of bovine α-thrombin are studied using the analysis of the Raman spectral features in the spectral interval 500–550 cm−1. The changes under study are caused by the transitions from lyophilized state to the native solution in PBS with a protein concentration of 2.8 mM (100 mg/ml) and from native solution to solution with partially reduced disulfide bridges. The reduction takes place when dithiothreitol (DTT) is added to the sample.
- Published
- 2014
39. PeptoGrid—Rescoring Function for AutoDock Vina to Identify New Bioactive Molecules from Short Peptide Libraries
- Author
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Alexander Zlobin, Roman V. Reshetnikov, Vasilina R. Gedzun, Maxim L. Lovat, Andrey V. Golovin, Arthur O. Zalevsky, Anton V. Malyshev, Gennady A. Babkin, and Igor Doronin
- Subjects
Bioactive molecules ,Pharmaceutical Science ,Peptide ,gabab receptor ,Computational biology ,Molecular Dynamics Simulation ,Analytical Chemistry ,Autodock vina ,lcsh:QD241-441 ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Organic chemistry ,Peptide Library ,Drug Discovery ,Animals ,Computer Simulation ,Physical and Theoretical Chemistry ,Zebrafish ,Peptide ligand ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Virtual screening ,rescoring ,Danio rerio ,Communication ,Organic Chemistry ,Reproducibility of Results ,Ligand (biochemistry) ,Molecular Docking Simulation ,chemistry ,Chemistry (miscellaneous) ,Docking (molecular) ,docking ,peptides ,Molecular Medicine ,Target protein ,Algorithms ,030217 neurology & neurosurgery - Abstract
Peptides are promising drug candidates due to high specificity and standout safety. Identification of bioactive peptides de novo using molecular docking is a widely used approach. However, current scoring functions are poorly optimized for peptide ligands. In this work, we present a novel algorithm PeptoGrid that rescores poses predicted by AutoDock Vina according to frequency information of ligand atoms with particular properties appearing at different positions in the target protein’s ligand binding site. We explored the relevance of PeptoGrid ranking with a virtual screening of peptide libraries using angiotensin-converting enzyme and GABAB receptor as targets. A reasonable agreement between the computational and experimental data suggests that PeptoGrid is suitable for discovering functional leads.
- Published
- 2019
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