Research Interests: Chemistry and glycophorin
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The membrane interface-partitioning region preceding the transmembrane anchor of the human immunodeficiency virus type 1 (HIV-1) gp41 envelope protein is one of the sites responsible for virus binding to its host cell membrane and... more
The membrane interface-partitioning region preceding the transmembrane anchor of the human immunodeficiency virus type 1 (HIV-1) gp41 envelope protein is one of the sites responsible for virus binding to its host cell membrane and subsequent fusion events. Here, we used molecular modeling techniques to assess membrane interactions, structure, and hydrophobic properties of the fusion-active peptide representing this region, several of its homologs from different HIV-1 strains, as well as a peptide - defective gp41 phenotype - unable to mediate cell-cell fusion and virus entry. It is shown that the wild-type peptides bind to the water-membrane interface in alpha-helical conformation, while the mutant adopts partly destabilized helix-break-helix structure on the membrane surface. The wild-type peptides reveal specific "tilted oblique-oriented" pattern of hydrophobicity on their surfaces - the property specific for fusion regions of other viruses. Fusion peptides penetrate into the membrane with their N-termini and reveal "fine-tuning" interactions with membrane and water environments: the shift of this balance (e.g., due to point mutations) may dramatically change the mode of membrane binding, and therefore, may cause loss of fusion activity. The modeling results agree well with experimental data and provide a strategy to delineate fusogenic regions in amino acid sequences of viral proteins.
Research Interests: Biophysics, Monte Carlo Simulation, Biology, Medicine, Molecular modeling, and 15 moreHumans, Sequence alignment, Cell fusion, Fusion, Peptides, Membrane, Gp, Human immunodeficiency virus, Protein Conformation, Amino Acid Sequence, Experimental Data, Biochemistry and cell biology, Structure Dynamics, Molecular Sequence Data, and Cell Membrane
Research Interests: Biophysics, Chemistry, Monte Carlo, Membrane Proteins, Medicine, and 15 moreMolecular Dynamics, Biological Sciences, Humans, Animals, Bacteriorhodopsin, Free Energy, Membrane, CHEMICAL SCIENCES, Antimicrobial Cationic Peptides, Lipid bilayers, Amino Acid Sequence, Lipid Bilayer, Conformational Isomerism, Molecular Sequence Data, and Molecular dynamic
The chemokine receptor CCR5 functions as a major fusion coreceptor for macrophage-tropic human immunodeficiency virus entry into cell. Here we report a three-dimensional model of CCR5 built using molecular modeling approach. Because the... more
The chemokine receptor CCR5 functions as a major fusion coreceptor for macrophage-tropic human immunodeficiency virus entry into cell. Here we report a three-dimensional model of CCR5 built using molecular modeling approach. Because the virus binds to extracellular domain of the receptor, special attention was given to conformational flexibility, hydrogen bonding, and environmental polarity properties of this protein part. Such data were obtained in the result of molecular dynamics study of the extracellular domain. It was shown that during the simulation the extracellular segments form a compact globular domain with numerous long-range hydrogen bonds between them. First loop of the receptor stays quite rigid while N-terminal region and loops 2, 3 are rather flexible. A number of amino acid residues disposed in unfavourable environment and, therefore, potentially involved in binding of CCR5 to viral glycoproteins and chemokines, was delineated. Comparison of the results with available experimental data permits a proposal that such residues in loop-1 and N-terminal part of the receptor are important for HIV-1 entry, while those in loops 2 and 3 participate in ligand binding. Perspectives of rational alteration of virus-binding activity of CCR5 are discussed.
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Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies,... more
Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions. In this work, using high-resolution NMR spectroscopy supported by atomistic computer modeling, conformational variability of the transmembrane domains and their interactions with surrounding lipids were found to differ significantly between representatives of the subfamily. Therefore, we suggest that the heterogeneous and highly dynamic membrane environment should be taken into account in the observed diversity of the structural/dynamic organization and mechanisms of activation of InsR, IGF1R, and IRR receptors...
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To date, a number of lantibiotics have been shown to use lipid II—a highly conserved peptidoglycan precursor in the cytoplasmic membrane of bacteria—as their molecular target. The α-component (Lchα) of the two-component lantibiotic... more
To date, a number of lantibiotics have been shown to use lipid II—a highly conserved peptidoglycan precursor in the cytoplasmic membrane of bacteria—as their molecular target. The α-component (Lchα) of the two-component lantibiotic lichenicidin, previously isolated from the Bacillus licheniformis VK21 strain, seems to contain two putative lipid II binding sites in its N-terminal and C-terminal domains. Using NMR spectroscopy in DPC micelles, we obtained convincing evidence that the C-terminal mersacidin-like site is involved in the interaction with lipid II. These data were confirmed by the MD simulations. The contact area of lipid II includes pyrophosphate and disaccharide residues along with the first isoprene units of bactoprenol. MD also showed the potential for the formation of a stable N-terminal nisin-like complex; however, the conditions necessary for its implementation in vitro remain unknown. Overall, our results clarify the picture of two component lantibiotics mechanism ...
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In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues - "hot spots"... more
In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues - "hot spots" that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation. I679A + A680G channel was severely toxic for oocytes most probably due to abnormally increased basal activity of the channel ("always open" gates). The replacement K688G presumably facilitated movements of TRP domain and disturbed its coupling to the pore, thus leading to spontaneous activation and enhanced desensitization of the channel. Finally, mutation K688P was suggested to impair TRP domain directed movement, and the mutated channel showed ~100-fold less sensitivity to the capsaicin, enhanced desensitization and weaker activation by the heat. Our results provide a better understanding of TRPV1 thermal and capsaicin-induced activation and gating. These observations provide a structural basis for understanding some aspects of TRPV1 channel functioning and depict potentially pathogenic mutations.
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Research Interests: Chemistry and torpedo ink
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Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype... more
Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a 'three-finger' fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC50 ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at high...
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Research Interests: Biochemistry, Chemistry, Phospholipids, Medicine, Circular Dichroism, and 15 moreLiposomes, Peptides, Liposome, Peptide, Membrane, Antimicrobial Cationic Peptides, Protein Secondary Structure Prediction, Lipid bilayers, Amino Acid Sequence, Melittin, Protein Binding, Cations, Biochemistry and cell biology, Sialic Acids, and Molecular Sequence Data
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Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and... more
Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop (loop-2) were determined by X-ray crystallography. The “water” conformation of the loop was frequently observed. It was similar to the structure of loop-2 of numerous CTs, determined by either NMR spectroscopy in aqueous solution, or the X-ray method. The “membrane” conformation is rare one and, to date has only been observed by NMR for a single cytotoxin 1 from N. oxiana (CT1No) in detergent micelle. Both CT13Nn and CT1No are S-type CTs. Membrane-binding of these CTs probably involves an additional step—the conformational transformation of the loop-2. To confirm this suggestion, we conducted molecular dynamics simulations of both CT1No and CT13Nn in the Highly Mimetic Membrane Model of palmitoiloleoylphosphat...
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S-acylation is a post-translational linkage of long chain fatty acids to cysteines, playing a key role in normal physiology and disease. In human cells, the reaction is catalyzed by a family of 23 membrane DHHC-acyltransferases (carrying... more
S-acylation is a post-translational linkage of long chain fatty acids to cysteines, playing a key role in normal physiology and disease. In human cells, the reaction is catalyzed by a family of 23 membrane DHHC-acyltransferases (carrying an Asp-His-His-Cys catalytic motif) in two stages: (1) acyl-CoA-mediated autoacylation of the enzyme; and (2) further transfer of the acyl chain to a protein substrate. Despite the availability of a 3D-structure of human acyltransferase (hDHHC20), the molecular aspects of lipid selectivity of DHHC-acyltransferases remain unclear. In this paper, using molecular dynamics (MD) simulations, we studied membrane-bound hDHHC20 right before the acylation by C12-, C14-, C16-, C18-, and C20-CoA substrates. We found that: (1) regardless of the chain length, its terminal methyl group always reaches the “ceiling” of the enzyme’s cavity; (2) only for C16, an optimal “reactivity” (assessed by a simple geometric criterion) permits the autoacylation; (3) in MD, some...
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Understanding fusion mechanisms employed by SARS-CoV-2 spike protein entails realistic transmembrane domain (TMD) models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we... more
Understanding fusion mechanisms employed by SARS-CoV-2 spike protein entails realistic transmembrane domain (TMD) models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD only based on its primary structure. We performed amino acid sequence pattern matching and compared the molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and selected an appropriate template for homology modeling. We then iteratively built a model of spike TMD, adjusting “dynamic MHP portraits” and residue variability motifs. The stability of this model, with and without palmitoyl modifications downstream of the TMD, and several alternative configurations (including a recent NMR structure), was tested in all-atom molecular dynamics simulations in a POPC bilayer mimicking the viral envelope. Our model demonstrated...
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Lipid modification of viral proteins with fatty acids of different lengths (S-acylation) is crucial for virus pathogenesis. The reaction is catalyzed by members of the DHHC family and proceeds in two steps: the autoacylation is followed... more
Lipid modification of viral proteins with fatty acids of different lengths (S-acylation) is crucial for virus pathogenesis. The reaction is catalyzed by members of the DHHC family and proceeds in two steps: the autoacylation is followed by the acyl chain transfer onto protein substrates. The crystal structure of human DHHC20 (hDHHC20), an enzyme involved in the acylation of S-protein of SARS-CoV-2, revealed that the acyl chain may be inserted into a hydrophobic cavity formed by four transmembrane (TM) α-helices. To test this model, we used molecular dynamics of membrane-embedded hDHHC20 and its mutants either in the absence or presence of various acyl-CoAs. We found that among a range of acyl chain lengths probed only C16 adopts a conformation suitable for hDHHC20 autoacylation. This specificity is altered if the small or bulky residues at the cavity’s ceiling are exchanged, e.g., the V185G mutant obtains strong preferences for binding C18. Surprisingly, an unusual hydrophilic ridge...
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Unsaturated phosphatidylserine (PS) bilayers are widely used in experimental studies of peptides and proteins in charged membranes. Atomic-scale details of peptide-membrane interactions may be assessed via molecular dynamics (MD)... more
Unsaturated phosphatidylserine (PS) bilayers are widely used in experimental studies of peptides and proteins in charged membranes. Atomic-scale details of peptide-membrane interactions may be assessed via molecular dynamics (MD) simulations. Unfortunately, a wide application of computational techniques to such systems is limited because of serious technical problems related to correct treatment of long-range electrostatic effects. Here we present a new model of full-atom hydrated PS bilayer. It consists of 128 molecules of 1,2-dioleoyl-snglycero-3-phosphoserine (DOPS), 128 Na+ counterions, and explicit waters. The system was subjected to 15-ns MD simulations with different algorithms of electrostatics treatment (cutoff function and particle mesh Ewald summation (PME)). As a result, an optimal PME-based MD-protocol was elaborated. It provides a good agreement between the macroscopic averages calculated for the equilibrium part of the MD trajectory and those available from experiments. The model of the DOPS bilayer was used to study interactions with penetratin (pAntp). pAntp is a 16-residue peptide that is capable of passing through cell membranes and negatively charged phospholipid vesicles without their leakage. Unfortunately, the mechanism of penetration is still insufficiently understood. During the simulations, a free adsorption of pAntp on the water-lipid interface was observed. The membrane binding of pAntp was accompanied by distortion of its initial α-helical conformation. The critical roles of individual amino acid residues and surface charge of the DOPS bilayer were delineated. It was shown that the peptide-induced perturbation of the membrane had a local character.
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This review surveys recent achievements of molecular computer modeling in understanding spatial structure, dynamics, and mechanisms of functioning of transmembrane α-helical dimers in membranes. The factors driving self-association of... more
This review surveys recent achievements of molecular computer modeling in understanding spatial structure, dynamics, and mechanisms of functioning of transmembrane α-helical dimers in membranes. The factors driving self-association of hydrophobic helices in the membrane milieu are considered with examples of their applications to biologically relevant problems. The emphasis is made on the recent results, which help to understand important aspects of structure-function relations for these systems and their biological activity. Limitations and shortcomings of the methods, along with their perspectives in design of new membrane active agents, are discussed.
Research Interests: Thermodynamics, Structural Dynamics, Membrane Proteins, Molecular Computing, Humans, and 12 moreComputer Simulation, Protein Chemistry, Free Energy, Protein Conformation, Spatial structure, Biological activity, Structure Function, Coarse Grained Soil, Monte Carlo Method, Receptor Tyrosine Kinase, Cell Membrane, and Molecular dynamic
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Membrane and membrane-active peptides and proteins play a crucial role in numerous cell processes, such as signaling, ion conductance, fusion, and others. Many of them act as highly specific and efficient drugs or drug targets, and,... more
Membrane and membrane-active peptides and proteins play a crucial role in numerous cell processes, such as signaling, ion conductance, fusion, and others. Many of them act as highly specific and efficient drugs or drug targets, and, therefore, attract growing interest of medicinal chemists. Because of experimental difficulties with characterization of their spatial structure and mode of membrane binding, essential attention is given now to molecular modeling techniques. During the last years an important progress has been achieved in molecular dynamics (MD) and Monte Carlo (MC) simulations of peptides and proteins with explicit and/or implicit theoretical models of membranes. The first ones allow atomic-resolution studies of peptides behavior on the membrane-water interfaces. Models with implicit consideration of membrane are of a special interest because of their computational efficiency and ability to account for principal trends in protein-lipid interactions. In this approximation, the bilayer is usually treated as continuum whose properties vary along the membrane thickness, and membrane insertion is simulated using either MC or MD methods. This review surveys recent applications of both types of lipid bilayer models in computer simulations of a wide variety of peptides and proteins with different biological activities. Theoretical background of the membrane models is considered with examples of their applications to biologically relevant problems. The emphasis of the review is made on recent MC and MD computations, on structural and/or functional information, which may be obtained via molecular modeling. The approximations and shortcomings of the models, along with their perspectives in design of new membrane active drugs, are discussed.
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To understand the initial stages of membrane destabilization induced by viral proteins, the factors important for binding of fusion peptides to cell membranes must be identified. In this study, effects of lipid composition on the mode of... more
To understand the initial stages of membrane destabilization induced by viral proteins, the factors important for binding of fusion peptides to cell membranes must be identified. In this study, effects of lipid composition on the mode of peptides&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; binding to membranes are explored via molecular dynamics (MD) simulations of the peptide E5, a water-soluble analogue of influenza hemagglutinin fusion peptide, in two full-atom hydrated lipid bilayers composed of dimyristoyl- and dipalmitoylphosphatidylcholine (DMPC and DPPC, respectively). The results show that, although the peptide has a common folding motif in both systems, it possesses different modes of binding. The peptide inserts obliquely into the DMPC membrane mainly with its N-terminal alpha helix, while in DPPC, the helix lies on the lipid/water interface, almost parallel to the membrane surface. The peptide seriously affects structural and dynamical parameters of surrounding lipids. Thus, it induces local thinning of both bilayers and disordering of acyl chains of lipids in close proximity to the binding site. The &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;membrane response&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; significantly depends upon lipid composition: distortions of DMPC bilayer are more pronounced than those in DPPC. Implications of the observed effects to molecular events on initial stages of membrane destabilization induced by fusion peptides are discussed.
Research Interests: Biochemistry, Chemistry, Protein Folding, Medicine, Software, and 11 moreComputer Simulation, Peptides, Membrane Lipids, Peptide, Membrane, Protein Secondary Structure Prediction, Protein Binding, Static Electricity, Biochemistry and cell biology, Cell Membrane, and Medical biochemistry and metabolomics
Research Interests: Kinetics, Biology, Apoptosis, Medicine, Biological Sciences, and 15 moreCaspases, Antioxidants, Electron Transfer, Animals, Cytochrome C, Horses, Biochemical, CHEMICAL SCIENCES, Antioxidant Activity, Protein Secondary Structure Prediction, Rats, Amino Acid Sequence, Amino Acid Substitution Rates, Recombinant Proteins, and Medical and Health Sciences
Research Interests: Chemical Engineering, Chemistry, Medicine, Molecular modeling, Influenza virus, and 15 moreBiological Sciences, influenza A, Biopolymers, Physical sciences, Membrane Fusion, Enzyme, Hemagglutinin, NP, Group, influenza A virus, Amino Acid Sequence, Polyacrylamide Gel Electrophoresis, Biochemistry and cell biology, Molecular Sequence Data, and Sodium Dodecyl Sulfate
Research Interests: Engineering, Biophysics, Chemistry, Kinetics, Membrane Proteins, and 15 morePhysical sciences, Peptides, The, Peptide, Membrane, CHEMICAL SCIENCES, Amino Acids, Hydrogen Bonding, Surface Properties, Molecular Conformation, Protein Conformation, Lipid bilayers, Cell Membrane, binding sites, and Heterogeneous environment
Structurally similar catalytic subunits A of ricin (RTA) and viscumin (MLA) exhibit cytotoxic activity through ribosome inactivation. Ricin is more cytotoxic than viscumin, although the molecular mechanisms behind this difference are... more
Structurally similar catalytic subunits A of ricin (RTA) and viscumin (MLA) exhibit cytotoxic activity through ribosome inactivation. Ricin is more cytotoxic than viscumin, although the molecular mechanisms behind this difference are still poorly understood. To shed more light on this problem, we used a combined biochemical/molecular modeling approach to assess possible relationships between the activity of toxins and their structural/dynamic properties. Based on bioassay measurements, it was suggested that the differences in activity are associated with the ability of RTA and MLA to undergo structural/hydrophobic rearrangements during trafficking through the endoplasmic reticulum (ER) membrane. Molecular dynamics simulations and surface hydrophobicity mapping of both proteins in different media showed that RTA rearranges its structure in a membrane-like environment much more efficiently than MLA. Their refolded states also drastically differ in terms of hydrophobic organization. We...