Papers by Valeri Barsegov
Botulinum Endopeptidase: SAXS Experiments and MD Simulations Reveal Extended Solution Structures That Account for Its Biochemical Properties
The Journal of Physical Chemistry B
The PLATELET INTEGRIN αIIbβ3 CHANGES FROM A LOWER- to A Higher-AFFINITY STATE DURING INTERACTION with FIBRINOGEN
Blood
1130 The integrin αIIbβ3 (GPIIb-IIIa) plays an essential role in platelet adhesion and cohesion b... more 1130 The integrin αIIbβ3 (GPIIb-IIIa) plays an essential role in platelet adhesion and cohesion by binding to a number of adhesive ligands including fibrinogen, von Willebrand factor, fibronectin, and vitronectin. Following ligand binding, αIIbβ3-mediated intracellular signaling is thought to stabilize platelet adhesive interactions, cause platelet spreading, and initiate clot retraction. Here we investigated the time course of interactions between purified αIIbβ3 and its major ligand fibrinogen when both were firmly attached to apposed surfaces, mimicking αIIbβ3-mediated platelet adhesive interactions. To measure the mechanical resistance of individual αIIbβ3-fibrinogen complexes under a constant tensile force, we used a previously described optical trap force clamp system (Litvinov et al., Biophys. J., 2011, 100, 165). Briefly, we trapped a fibrinogen-coated microscopic bead in a focused laser beam and intermittently brought it into contact with an αIIbβ3-coated silica pedestal. R...
Molecular Mechanisms of Transition from Catch to Slip Bonds in Fibrin
Biophysical Journal
Atomic Structural Models of Fibrin Oligomers
Structure (London, England : 1993), Jan 5, 2018
The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin pol... more The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. When reaching a critical length, these intermediate species aggregate laterally to transform into fibers arranged into branched fibrin network. We combined multiscale modeling in silico with atomic force microscopy (AFM) imaging to reconstruct complete atomic models of double-stranded fibrin protofibrils with γ-γ crosslinking, A:a and B:b knob-hole bonds, and αC regions-all important structural determinants not resolved crystallographically. Structures of fibrin oligomers and protofibrils containing up to 19 monomers were successfully validated by quantitative comparison with high-resolution AFM images. We characterized the protofibril twisting, bending, kinking, and reversibility of A:a knob-hole bonds, and calculated hydrodynamic param...
Regulatory element in fibrin triggers tension-activated transition from catch to slip bonds
Proceedings of the National Academy of Sciences of the United States of America, Aug 21, 2018
Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal h... more Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal how mechanical load impacts fibrin, we carried out optical trap-based single-molecule forced unbinding experiments. The strength of noncovalent A:a knob-hole bond stabilizing fibrin polymers first increases with tensile force (catch bonds) and then decreases with force when the force exceeds a critical value (slip bonds). To provide the structural basis of catch-slip-bond behavior, we analyzed crystal structures and performed molecular modeling of A:a knob-hole complex. The movable flap (residues γ295 to γ305) containing the weak calcium-binding site γ2 serves as a tension sensor. Flap dissociation from the B domain in the γ-nodule and translocation to knob 'A' triggers hole 'a' closure, resulting in the increase of binding affinity and prolonged bond lifetimes. The discovery of biphasic kinetics of knob-hole bond rupture is quantitatively explained by using a theory, form...
Dynamic Transition from α-Helices to β-Sheets in Polypeptide Coiled-Coil Motifs
Journal of the American Chemical Society, Nov 15, 2017
We carried out dynamic force manipulations in silico on a variety of coiled-coil protein fragment... more We carried out dynamic force manipulations in silico on a variety of coiled-coil protein fragments from myosin, chemotaxis receptor, vimentin, fibrin, and phenylalanine zippers that vary in size and topology of their α-helical packing. When stretched along the superhelical axis, all superhelices show elastic, plastic, and inelastic elongation regimes and undergo a dynamic transition from the α-helices to the β-sheets, which marks the onset of plastic deformation. Using the Abeyaratne-Knowles formulation of phase transitions, we developed a new theoretical methodology to model mechanical and kinetic properties of protein coiled-coils under mechanical nonequilibrium conditions and to map out their energy landscapes. The theory was successfully validated by comparing the simulated and theoretical force-strain spectra. We derived the scaling laws for the elastic force and the force for α-to-β transition, which can be used to understand natural proteins' properties as well as to rati...
Comparison of the RGD- and AGDV-Containing Peptide Interactions with the Platelet Integrin Alphaiibbeta3
Biophysical Journal
Conformational Flexibility and Self-Association of Fibrinogen in Concentrated Solutions
The Journal of Physical Chemistry B
Dynamics of microtubules: highlights of recent computational and experimental investigations
Journal of physics. Condensed matter : an Institute of Physics journal, Jan 16, 2017
Microtubules are found in most eukaryotic cells, with homologs in eubacteria and archea, and they... more Microtubules are found in most eukaryotic cells, with homologs in eubacteria and archea, and they have functional roles in mitosis, cell motility, intracellular transport, and the maintenance of cell shape. Numerous efforts have been expended over the last two decades to characterize the interactions between microtubules and the wide variety of microtubule associated proteins that control their dynamic behavior in cells resulting in microtubules being assembled and disassembled where and when they are required by the cell. We present the main findings regarding microtubule polymerization and depolymerization and review recent work about the molecular motors that modulate microtubule dynamics by inducing either microtubule depolymerization or severing. We also discuss the main experimental and computational approaches used to quantify the thermodynamics and mechanics of microtubule filaments.
Mechanistic Basis for the Binding of RGD- and AGDV-Peptides to the Platelet Integrin αIIbβ3
Biochemistry, 2017
Structural Basis of Interfacial Flexibility in Fibrin Oligomers
Structure (London, England : 1993), Nov 28, 2016
Fibrin is a filamentous network made in blood to stem bleeding; it forms when fibrinogen is conve... more Fibrin is a filamentous network made in blood to stem bleeding; it forms when fibrinogen is converted into fibrin monomers that self-associate into oligomers and then to polymers. To gather structural insights into fibrin formation and properties, we combined high-resolution atomic force microscopy of fibrin(ogen) oligomers and molecular modeling of crystal structures of fibrin(ogen) and its fragments. We provided a structural basis for the intermolecular flexibility of single-stranded fibrin(ogen) oligomers and identified a hinge region at the D:D inter-monomer junction. Following computational reconstruction of the missing portions, we recreated the full-atomic structure of double-stranded fibrin oligomers that was validated by quantitative comparison with the experimental images. We characterized previously unknown intermolecular binding contacts at the D:D and D:E:D interfaces, which drive oligomerization and reinforce the intra- and inter-strand connections in fibrin besides th...
Assembly and mechanical properties of the cargo-free and cargo-loaded bacterial nanocompartment encapsulin
Biomacromolecules, 2016
SOP-GPU: influence of solvent-induced hydrodynamic interactions on dynamic structural transitions in protein assemblies
Journal of computational chemistry, Jan 26, 2016
Hydrodynamic interactions (HI) are incorporated into Langevin dynamics of the Cα -based protein m... more Hydrodynamic interactions (HI) are incorporated into Langevin dynamics of the Cα -based protein model using the Truncated Expansion approximation (TEA) to the Rotne-Prager-Yamakawa diffusion tensor. Computational performance of the obtained GPU realization demonstrates the model's capability for describing protein systems of varying complexity (10(2) -10(5) residues), including biological particles (filaments, virus shells). Comparison of numerical accuracy of the TEA versus exact description of HI reveals similar results for the kinetics and thermodynamics of protein unfolding. The HI speed up and couple biomolecular transitions through cross-communication among protein domains, which result in more collective displacements of structure elements governed by more deterministic (less variable) dynamics. The force-extension/deformation spectra from nanomanipulations in silico exhibit sharper force signals that match well the experimental profiles. Hence, biomolecular simulations w...
Dissociation of Bimolecular aIIb �3-Fibrinogen Complex under a Constant Tensile Force
Biophys J, 2011
Mechanical Unbinding of A� Peptides from Amyloid Fibrils
J Mol Biol, 2007
JBC 2013-KKO vs RTO-supplement
American Society of Hematology
Regulatory element in fibrin triggers tension-activated transition from catch to slip bonds
Proceedings of the National Academy of Sciences of the United States of America, Aug 21, 2018
Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal h... more Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal how mechanical load impacts fibrin, we carried out optical trap-based single-molecule forced unbinding experiments. The strength of noncovalent A:a knob-hole bond stabilizing fibrin polymers first increases with tensile force (catch bonds) and then decreases with force when the force exceeds a critical value (slip bonds). To provide the structural basis of catch-slip-bond behavior, we analyzed crystal structures and performed molecular modeling of A:a knob-hole complex. The movable flap (residues γ295 to γ305) containing the weak calcium-binding site γ2 serves as a tension sensor. Flap dissociation from the B domain in the γ-nodule and translocation to knob 'A' triggers hole 'a' closure, resulting in the increase of binding affinity and prolonged bond lifetimes. The discovery of biphasic kinetics of knob-hole bond rupture is quantitatively explained by using a theory, form...
Regulatory element in fibrin triggers tension-activated transition from catch to slip bonds
Proceedings of the National Academy of Sciences of the United States of America, Aug 21, 2018
Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal h... more Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal how mechanical load impacts fibrin, we carried out optical trap-based single-molecule forced unbinding experiments. The strength of noncovalent A:a knob-hole bond stabilizing fibrin polymers first increases with tensile force (catch bonds) and then decreases with force when the force exceeds a critical value (slip bonds). To provide the structural basis of catch-slip-bond behavior, we analyzed crystal structures and performed molecular modeling of A:a knob-hole complex. The movable flap (residues γ295 to γ305) containing the weak calcium-binding site γ2 serves as a tension sensor. Flap dissociation from the B domain in the γ-nodule and translocation to knob 'A' triggers hole 'a' closure, resulting in the increase of binding affinity and prolonged bond lifetimes. The discovery of biphasic kinetics of knob-hole bond rupture is quantitatively explained by using a theory, form...
Quantum decoherence and time symmetry breaking. Quantum-classical correspondence in non-adiabatic transitions
Recent development of the complex spectral representations of the Liouville-von Neumann operator ... more Recent development of the complex spectral representations of the Liouville-von Neumann operator shows that irreversibility is a rigorous dynamical process taking place outside Hilbert space in the thermodynamic limit. In the present work this spectral representation is applied to the decoherence problem in quantum Brownian motion. In contrast to the path-integral method, often used in the context of quantum decoherence
Uploads
Papers by Valeri Barsegov