Biomedical subjects

V Barsegov

Publications and source records attributed to V Barsegov.

8 recordsLinked to original sources

PubMed2006

Dynamic competition between catch and slip bonds in selectins bound to ligands.

Atomic force measurements of unbinding rates (or off-rates) of ligands bound to a class of cell adhesion molecules from the selectin family show a transition from catch to slip bonds as the value of external force (f) is increased. At low forces (<10 pN), the unbinding rates decrease (catch regime), while, at high forces, the rates increase in accord with the Bell model (slip regime). The energy landscape underlying the catch-slip transition can be captured by a two-state model that considers the possibility of redistribution of population from the force-free bound state to the force-stabilized bound state. The excellent agreement between theory and experiments is used to extract the parameters characterizing the energy landscape of the complex by fitting the calculated curves to lifetime data (obtained at constant f) for the monomeric form of PSGL-1 (sPSGL-1). We used the constant force parameters to predict the distributions of unbinding times and unbinding forces as a function of the loading rate. The general two-state model, which also correctly predicts the absence of catch bonds in the binding of antibodies to selectins, is used to resolve the energy landscape parameters characterizing adhesive interactions of P- and L-selectins with physiological ligands such as sPSGL-1 and endoglycan and antibodies such as G1 and DREG56. Despite high sequence similarity, the underlying shapes of the energy landscape of P-selectin and L-selectin interacting with sPSGL-1 are markedly different. The underlying energy landscape of the selectin cell adhesion complex is sensitive to the nature of the ligand. The unified description of selectins bound to physiological ligands and antibodies in conjunction with experimental data can be used to extract the key parameters that describe the dynamics of cell adhesion complexes.

Binding, Competitive↗

PubMed2006

Mapping the energy landscape of biomolecules using single molecule force correlation spectroscopy: theory and applications.

We present, to our knowledge, a new theory that takes internal dynamics of proteins into account to describe forced-unfolding and force-quench refolding in single molecule experiments. In the current experimental setup (using either atomic force microscopy or laser optical tweezers) the distribution of unfolding times, P(t), is measured by applying a constant stretching force f(S) from which the apparent f(S)-dependent unfolding rate is obtained. To describe the complexity of the underlying energy landscape requires additional probes that can incorporate the dynamics of tension propagation and relaxation of the polypeptide chain upon force quench. We introduce a theory of force correlation spectroscopy to map the parameters of the energy landscape of proteins. In force correlation spectroscopy, the joint distribution P(T, t) of folding and unfolding times is constructed by repeated application of cycles of stretching at constant f(S) separated by release periods T during which the force is quenched to f(Q) < f(S). During the release period, the protein can collapse to a manifold of compact states or refold. We show that P(T, t) at various f(S) and f(Q) values can be used to resolve the kinetics of unfolding as well as formation of native contacts. We also present methods to extract the parameters of the energy landscape using chain extension as the reaction coordinate and P(T, t). The theory and a wormlike chain model for the unfolded states allows us to obtain the persistence length l(p) and the f(Q)-dependent relaxation time, giving us an estimate of collapse timescale at the single molecular level, in the coil states of the polypeptide chain. Thus, a more complete description of landscape of protein native interactions can be mapped out if unfolding time data are collected at several values of f(S) and f(Q). We illustrate the utility of the proposed formalism by analyzing simulations of unfolding-refolding trajectories of a coarse-grained protein (S1) with beta-sheet architecture for several values of f(S), T, and f(Q) = 0. The simulations of stretch-relax trajectories are used to map many of the parameters that characterize the energy landscape of S1.

Biomechanical Phenomena↗

PubMed2005

Influence of surface interactions on folding and forced unbinding of semiflexible chains.

We have investigated the folding and forced unbinding transitions of adsorbed semiflexible polymer chains using theory and simulations. These processes describe, at an elementary level, a number of biologically relevant phenomena that include adhesive interactions between proteins and tethering of receptors to cell walls. The binding interface is modeled as a solid surface, and the wormlike chain (WLC) is used for the semiflexible chain (SC). Using Langevin simulations, in the overdamped limit we examine the ordering kinetics of racquet-like and toroidal structures in the presence of an attractive interaction between the surface and the polymer chain. For a range of interactions, temperature, and the persistence length, l(p), we obtained the monomer density distribution, n(x), (x is the perpendicular distance of a tagged chain end from the surface) for all of the relevant morphologies. There is a single peak in n(x) inside the range of attractive forces, b, for chains in the extended conformations, whereas in racquet and toroidal structures there is an additional peak at x approximately b. The simulated results for n(x) are in good agreement with theory. The formation of toroids on the surface appears to be a first-order transition as evidenced by the bimodal distribution in n(x). The theoretical result underestimates the simulated n(x) for x << b and follows n(x) closely for x >/= b; the calculated density agrees exactly with n(x) in the range x << b. The chain-surface interaction is probed by subjecting the surface structures to a pulling force, f. The average extension, x( f), as a function of f exhibits a sigmoidal profile with sharp all-or-none transition at the unfolding force threshold f = f(c) which increases for more structured states. Simulated x(f) compare well with the theoretical predictions. The critical force, f(c), is a function of l(s)/l(c) for a fixed temperature, where l(c) and l(s) are the length scales that express the strength of the intramolecular and SC-surface attraction, respectively. For a fixed l(s), f(c) increases as l(p) decreases.

Adsorption↗

PubMed2005

Probing protein-protein interactions by dynamic force correlation spectroscopy.

We develop a formalism for single molecule dynamic force spectroscopy to map the energy landscape of protein-protein complex (P(1)P(2)). The joint distribution P(tau(1),tau(2)) of unbinding lifetimes tau(1) and tau(2), measurable in a compression-tension cycle, which accounts for the internal relaxation dynamics of the proteins under tension, shows that the histogram of tau(1) is not Poissonian. The theory is applied to the forced unbinding of protein P1, modeled as a wormlike chain, from P(1)P(2). We propose a new class of experiments which can resolve the effect of internal protein dynamics on the unbinding lifetimes.

Biophysics↗

PubMed2005

Dynamics of unbinding of cell adhesion molecules: transition from catch to slip bonds.

The unbinding dynamics of complexes involving cell-adhesion molecules depends on the specific ligands. Atomic force microscopy measurements have shown that for the specific P-selectin-P-selectin glycoprotein ligand (sPSGL-1) the average bond lifetime t initially increases (catch bonds) at low (< or =10 pN) constant force, f, and decreases when f > 10 pN (slip bonds). In contrast, for the complex with G1 anti-P-selectin monoclonal antibody t monotonically decreases with f. To quantitatively map the energy landscape of such complexes we use a model that considers the possibility of redistribution of population from one force-free state to another force-stabilized bound state. The excellent agreement between theory and experiments allows us to extract energy landscape parameters by fitting the calculated curves to the lifetime measurements for both sPSGL-1 and G1. Surprisingly, the unbinding transition state for P-selectin-G1 complex is close (0.32 nm) to the bound state, implying that the interaction is brittle, i.e., once deformed, the complex fractures. In contrast, the unbinding transition state of the P-selectin-sPSGL-1 complex is far (approximately 1.5 nm) from the bound state, indicative of a compliant structure. Constant f energy landscape parameters are used to compute the distributions of unbinding times and unbinding forces as a function of the loading rate, rf. For a given rf, unbinding of sPSGL-1 occurs over a broader range of f with the most probable f being an order of magnitude less than for G1. The theory for cell adhesion complexes can be used to predict the outcomes of unbinding of other protein-protein complexes.

Ligands↗

PubMed2002

Quantum decoherence, Zeno process, and time symmetry breaking.

The complex spectral representation of the Liouville-von Neumann operator outside Hilbert space 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 for the case where the environment surrounding the Brownian particle (subsystem) is in thermal equilibrium, our spectral representation is applicable to systems far from equilibrium, including a pure state for the surrounding bath. Starting with this pure initial condition, the subsystem evolves in time obeying a diffusion-type kinetic equation. Hence, the collapse of wave functions is a dynamical phenomenon occurring outside Hilbert space, and is not simply a contamination of the subsystem, a popular view accepted in the so-called "environmental" approach, by the mixed nature of the thermal bath. The essential element in the understanding of quantum decoherence is the "extensivity" of quantities characterizing the thermodynamic limit. Quantum Zeno time is shown to be a lower bound of the decoherence time.

Journal Article↗

PubMed1999

Kinetic studies of the delta-opioid antagonist [3H]DPN induced receptor binding on suspensions of mouse splenocytes.

Kinetic studies of binding of the delta-opioid antagonist [3H]DPN with receptors of mouse splenocytes are performed. Kinetic analysis of experimental data has shown that receptors of these cells possess activity toward the delta-opioid ligands. Presence of compounds that inhibit the conjugation of receptors with G-proteins, reduces receptor binding. Experimental data are computer simulated, and numerical values for various equilibrium as well as kinetic parameters of receptor binding and the G-protein cycle are obtained.

Animals↗

PubMed1998

On the kinetic theory of the extracellular signal transduction in native cells: I. Hormone-receptor interaction.

The hormone-receptor interaction is reconsidered and a minimal kinetic theory for the signal transduction in native cells is proposed. The basic equation for the time evolution of the concentration of the hormone-receptor complex is obtained. It is shown, that the hormone-receptor interaction is regulated by a cycle of G protein, i.e. kinetic parameters associated with the G protein cycle enter this equation. The existence of exponential and oscillatory regimes in kinetics of the G protein cycle, and hormone-receptor interactions are predicted. Experimental kinetic curves for agonist binding are computer-simulated, and numerical values for various kinetic and equilibrium parameters are obtained.

Enkephalin, Leucine-2-Alanine↗