Biomedical subjects

Yonathan Kozlovsky

Publications and source records attributed to Yonathan Kozlovsky.

5 recordsLinked to original sources

PubMed2004

Stalk phase formation: effects of dehydration and saddle splay modulus.

One of the earliest lipid intermediates forming in the course of membrane fusion is the lipid stalk. Although many aspects of the stalk hypothesis were elaborated theoretically and confirmed by experiments it remained unresolved whether stalk formation is always an energy consuming process or if there are conditions where the stalks are energetically favorable and form spontaneously resulting in an equilibrium stalk phase. Motivated by a recent breakthrough experiments we analyze the physical factors determining the spontaneous stalk formation. We show that this process can be driven by interplay between two factors: the elastic energy of lipid monolayers including a contribution of the saddle splay deformation and the energy of hydration repulsion acting between apposing membranes. We analyze the dependence of stalk formation on the saddle splay (Gaussian) modulus of the lipid monolayers and estimate the values of this modulus based on the experimentally established phase boundary between the lamellar and the stalk phases. We suggest that fusion proteins can induce stalk formation just by bringing the membranes into close contact, and accumulating, at least locally, a sufficiently large energy of the hydration repulsion.

Cell Surface Extensions↗

PubMed2004

Orientation and interaction of oblique cylindrical inclusions embedded in a lipid monolayer: a theoretical model for viral fusion peptides.

We consider the elastic behavior of flat lipid monolayer embedding cylindrical inclusions oriented obliquely with respect to the monolayer plane. An oblique inclusion models a fusion peptide, a part of a specialized protein capable of inducing merger of biological membranes in the course of fundamental cellular processes. Although the crucial importance of the fusion peptides for membrane merger is well established, the molecular mechanism of their action remains unknown. This analysis is aimed at revealing mechanical deformations and stresses of lipid monolayers induced by the fusion peptides, which, potentially, can destabilize the monolayer structure and enhance membrane fusion. We calculate the deformation of a monolayer embedding a single oblique inclusion and subject to a lateral tension. We analyze the membrane-mediated interactions between two inclusions, taking into account bending of the monolayer and tilt of the hydrocarbon chains with respect to the surface normal. In contrast to a straightforward prediction that the oblique inclusions should induce tilt of the lipid chains, our analysis shows that the monolayer accommodates the oblique inclusion solely by bending. We find that the interaction between two inclusions varies nonmonotonically with the interinclusion distance and decays at large separations as square of the distance, similar to the electrostatic interaction between two electric dipoles in two dimensions. This long-range interaction is predicted to dominate the other interactions previously considered in the literature.

Computer Simulation↗

PubMed2003

Membrane fission: model for intermediate structures.

Membrane budding-fission is a fundamental process generating intracellular carriers of proteins. Earlier works were focused only on formation of coated buds connected to the initial membrane by narrow membrane necks. We present the theoretical analysis of the whole pathway of budding-fission, including the crucial stage where the membrane neck undergoes fission and the carrier separates from the donor membrane. We consider two successive intermediates of the reaction: 1), a constricted membrane neck coming out of aperture of the assembling protein coat, and 2), hemifission intermediate resulting from self-fusion of the inner monolayer of the neck, while its outer monolayer remains continuous. Transformation of the constricted neck into the hemifission intermediate is driven by the membrane stress produced in the neck by the protein coat. Although apparently similar to hemifusion, the fission is predicted to have an opposite dependence on the monolayer spontaneous curvature. Analysis of the further stages of the process demonstrates that in all practically important cases the hemifission intermediate decays spontaneously into two separate membranes, thereby completing the fission process. We formulate the "job description" for fission proteins by calculating the energy they have to deliver and the radii of the protein coat aperture which have to be reached to drive the fission process.

Cell Surface Extensions↗

PubMed2002

Lipid intermediates in membrane fusion: formation, structure, and decay of hemifusion diaphragm.

Lipid bilayer fusion is thought to involve formation of a local hemifusion connection, referred to as a fusion stalk. The subsequent fusion stages leading to the opening of a fusion pore remain unknown. The earliest fusion pore could represent a bilayer connection between the membranes and could be formed directly from the stalk. Alternatively, fusion pore can form in a single bilayer, referred to as hemifusion diaphragm (HD), generated by stalk expansion. To analyze the plausibility of stalk expansion, we studied the pathway of hemifusion theoretically, using a recently developed elastic model. We show that the stalk has a tendency to expand into an HD for lipids with sufficiently negative spontaneous splay, (~)J(s)< 0. For different experimentally relevant membrane configurations we find two characteristic values of the spontaneous splay. (~)J*(s) and (~)J**(s), determining HD dimension. The HD is predicted to have a finite equilibrium radius provided that the spontaneous splay is in the range (~)J**(s)< (~)J(s)<(~)J*(s), and to expand infinitely for (~)J(s)<(~)J**(s). In the case of common lipids, which do not fuse spontaneously, an HD forms only under action of an external force pulling the diaphragm rim apart. We calculate the dependence of the HD radius on this force. To address the mechanism of fusion pore formation, we analyze the distribution of the lateral tension emerging in the HD due to the establishment of lateral equilibrium between the deformed and relaxed portions of lipid monolayers. We show that this tension concentrates along the HD rim and reaches high values sufficient to rupture the bilayer and form the fusion pore. Our analysis supports the hypothesis that transition from a hemifusion to a fusion pore involves radial expansion of the stalk.

Biophysical Phenomena↗

PubMed2002

Stalk model of membrane fusion: solution of energy crisis.

Membrane fusion proceeds via formation of intermediate nonbilayer structures. The stalk model of fusion intermediate is commonly recognized to account for the major phenomenology of the fusion process. However, in its current form, the stalk model poses a challenge. On one hand, it is able to describe qualitatively the modulation of the fusion reaction by the lipid composition of the membranes. On the other, it predicts very large values of the stalk energy, so that the related energy barrier for fusion cannot be overcome by membranes within a biologically reasonable span of time. We suggest a new structure for the fusion stalk, which resolves the energy crisis of the model. Our approach is based on a combined deformation of the stalk membrane including bending of the membrane surface and tilt of the hydrocarbon chains of lipid molecules. We demonstrate that the energy of the fusion stalk is a few times smaller than those predicted previously and the stalks are feasible in real systems. We account quantitatively for the experimental results on dependence of the fusion reaction on the lipid composition of different membrane monolayers. We analyze the dependence of the stalk energy on the distance between the fusing membranes and provide the experimentally testable predictions for the structural features of the stalk intermediates.

Biophysical Phenomena↗