Interbilayer forces in membrane fusion
Encyclopedia
Membrane fusion is a key biophysical process that is essential for the functioning of life itself. It is defined as the event where two lipid bilayers approach each other and then merge to form a single continuous structure. In living beings, cells are made of an outer coat made of lipid bilayers; which then cause fusion to take place in events such as fertilization, embryogenesis
and even infections by various types of bacteria
and viruses. It is therefore an extremely important event to study. From an evolutionary angle, fusion is an extremely controlled phenomenon. Random fusion can result in severe problems to the normal functioning of the human body. Regardless of the complexity of the system, fusion essentially occurs due to the interplay of various interfacial forces, namely hydration repulsion, hydrophobic attraction and van der Waals force
s. It is interesting to note here that in some cases, fusion is also mediated by proteins; nevertheless the interfacial forces mentioned above act in parallel with proteins on the cell surface to cause fusion. Hence, the underlying forces of membrane fusion essentially remain the same.
molecules consisting of a hydrophobic tail and a hydrophilic head group. Therefore, these structures experience all the characteristic Interbilayer forces involved in that regime.
(S.F.A), an instrument used for measuring forces between surfaces. This repulsion was first proposed by Langmuir
and was thought to arise due to water molecules that hydrate
the bilayers. Hydration repulsion can thus be defined as the work required in removing the water molecules around hydrophilic molecules (like lipid
head groups) in the bilayer system. As water molecules have an affinity towards hydrophilic head groups, they try to arrange themselves around the head groups of the lipid
molecules and it becomes very hard to separate this favorable combination.
Experiments performed through SFA have confirmed that the nature of this force is an exponential decline. The potential
VR is given by
where CR (>0) is a measure of the hydration interaction energy for hydrophilic molecules of the given system, λR is a characteristic length scale of hydration repulsion and z is the distance of separation. In other words, it is on distances up to this length that molecules/surfaces fully experience this repulsion.
of hydrophobic particles in water and play important roles in various biological phenomena including folding and stabilization of macromolecules such as proteins and fusion of cell membranes.
The potential VA is given by
where CA (<0) is a measure of the hydrophobic interaction energy for the given system, λA is a characteristic length scale of hydrophobic attraction and z is the distance of separation.
These forces arise due to dipole-dipole interactions (induced/permanent) between molecules of bilayers. As molecules come closer, this attractive force arises due to the ordering of these dipoles; like in the case of magnets that align and attract each other as they approach. This also implies that any surface would experience a van der waals attraction. In bilayers, the form taken by van der Waals interaction potential VVDW is given by
where H is the Hamaker constant
and D and z are the bilayers thickness and the distance of separation respectively.
head groups. However, it has been hard to exactly determine the connection between adhesion
, fusion and interbilayer forces. The forces that promote cell adhesion
are not the same as the ones that promote membrane fusion. Studies show that by creating a stress on the interacting bilayers, fusion can be achieved without disrupting the interbilayer interactions. It has also been suggested that membrane fusion takes place through a sequence of structural rearrangements that help to overcome the barrier that prevents fusion. Thus, interbilayer fusion takes place through
(SFA) indicate that membrane fusion can instantaneously occur when two bilayers are still at a finite distance from each other without them having to overcome the short-range repulsive force barrier. This is attributed to the molecular rearrangements that occur resulting in the bypassing of these forces by the membranes. During fusion, the hydrophobic tails of a small patch of lipids on the cell membrane
are exposed to the aqueous phase surrounding them. This results in very strong hydrophobic attractions (which dominate the repulsive force) between the exposed groups leading to membrane fusion. The attractive van der Waals forces play a negligible role in membrane fusion. Thus, fusion is a result of the hydrophobic attractions between internal hydrocarbon chain groups that are exposed to the normally inaccessible aqueous environment. Fusion is observed to start at points on the membranes where the membrane stresses are either the weakest or the strongest.
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
and even infections by various types of bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and viruses. It is therefore an extremely important event to study. From an evolutionary angle, fusion is an extremely controlled phenomenon. Random fusion can result in severe problems to the normal functioning of the human body. Regardless of the complexity of the system, fusion essentially occurs due to the interplay of various interfacial forces, namely hydration repulsion, hydrophobic attraction and van der Waals force
Van der Waals force
In physical chemistry, the van der Waals force , named after Dutch scientist Johannes Diderik van der Waals, is the sum of the attractive or repulsive forces between molecules other than those due to covalent bonds or to the electrostatic interaction of ions with one another or with neutral...
s. It is interesting to note here that in some cases, fusion is also mediated by proteins; nevertheless the interfacial forces mentioned above act in parallel with proteins on the cell surface to cause fusion. Hence, the underlying forces of membrane fusion essentially remain the same.
Inter-bilayer forces
Lipid bilayers are structures of lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
molecules consisting of a hydrophobic tail and a hydrophilic head group. Therefore, these structures experience all the characteristic Interbilayer forces involved in that regime.
Hydration repulsion
Two hydrated bilayers experience strong repulsion as they approach each other. These forces have been measured using the Surface forces apparatusSurface forces apparatus
The surface force apparatus is a scientific instrument and technique pioneered by D. Tabor, R.H.S. Winterton, J.N. Israelachvili in the early 1970s at Cambridge University...
(S.F.A), an instrument used for measuring forces between surfaces. This repulsion was first proposed by Langmuir
Irving Langmuir
Irving Langmuir was an American chemist and physicist. His most noted publication was the famous 1919 article "The Arrangement of Electrons in Atoms and Molecules" in which, building on Gilbert N. Lewis's cubical atom theory and Walther Kossel's chemical bonding theory, he outlined his...
and was thought to arise due to water molecules that hydrate
Hydrate
Hydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water. The chemical state of the water varies widely between hydrates, some of which were so labeled before their chemical structure was understood....
the bilayers. Hydration repulsion can thus be defined as the work required in removing the water molecules around hydrophilic molecules (like lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
head groups) in the bilayer system. As water molecules have an affinity towards hydrophilic head groups, they try to arrange themselves around the head groups of the lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
molecules and it becomes very hard to separate this favorable combination.
Experiments performed through SFA have confirmed that the nature of this force is an exponential decline. The potential
Potential
*In linguistics, the potential mood*The mathematical study of potentials is known as potential theory; it is the study of harmonic functions on manifolds...
VR is given by
where CR (>0) is a measure of the hydration interaction energy for hydrophilic molecules of the given system, λR is a characteristic length scale of hydration repulsion and z is the distance of separation. In other words, it is on distances up to this length that molecules/surfaces fully experience this repulsion.
Hydrophobic attraction
Hydrophobic forces are the attractive forces between any two hydrophobic groups in aqueous media, e.g. the forces between two long hydrocarbon chains in aqueous solutions. The magnitude of these forces depends on the hydrophobicity of the interacting groups as well as the distance separating them (they are found to decrease roughly exponentially with the distance). The physical origin of these forces is a debated issue but they have been found to be long-ranged and are the strongest among all the physical interaction forces operating between biological surfaces and molecules. Due to their long range nature, they are responsible for rapid coagulationCoagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
of hydrophobic particles in water and play important roles in various biological phenomena including folding and stabilization of macromolecules such as proteins and fusion of cell membranes.
The potential VA is given by
where CA (<0) is a measure of the hydrophobic interaction energy for the given system, λA is a characteristic length scale of hydrophobic attraction and z is the distance of separation.
van der Waals forces in bilayers
where H is the Hamaker constant
Hamaker Constant
The Hamaker constant A can be defined for a Van der Waals body-body interaction:A=\pi^2\times C \times \rho_1 \times \rho_2where \rho_1 and \rho_2 are the number of atoms per unit volume in two interacting bodies and C is the coefficient in the particle-particle pair interaction.The Hamaker...
and D and z are the bilayers thickness and the distance of separation respectively.
Background
For fusion to take place, it has to overcome huge repulsive forces due to the strong hydration repulsion between hydrophilic lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
head groups. However, it has been hard to exactly determine the connection between adhesion
Adhesion
Adhesion is any attraction process between dissimilar molecular species that can potentially bring them in close contact. By contrast, cohesion takes place between similar molecules....
, fusion and interbilayer forces. The forces that promote cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
are not the same as the ones that promote membrane fusion. Studies show that by creating a stress on the interacting bilayers, fusion can be achieved without disrupting the interbilayer interactions. It has also been suggested that membrane fusion takes place through a sequence of structural rearrangements that help to overcome the barrier that prevents fusion. Thus, interbilayer fusion takes place through
- local approach of membrane
- structural rearrangements causing hydrationHydrateHydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water. The chemical state of the water varies widely between hydrates, some of which were so labeled before their chemical structure was understood....
repulsion forces to be overcome - complete merging to form a single entity
Interbilayer interactions during membrane fusion
When two lipid bilayers approach each other, they experience weak van der Waals attractive forces and much stronger repulsive forces due to hydration repulsion. These forces are normally dominant over the hydrophobic attractive forces between the membranes. Studies done on membrane bilayers using Surface forces apparatusSurface forces apparatus
The surface force apparatus is a scientific instrument and technique pioneered by D. Tabor, R.H.S. Winterton, J.N. Israelachvili in the early 1970s at Cambridge University...
(SFA) indicate that membrane fusion can instantaneously occur when two bilayers are still at a finite distance from each other without them having to overcome the short-range repulsive force barrier. This is attributed to the molecular rearrangements that occur resulting in the bypassing of these forces by the membranes. During fusion, the hydrophobic tails of a small patch of lipids on the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
are exposed to the aqueous phase surrounding them. This results in very strong hydrophobic attractions (which dominate the repulsive force) between the exposed groups leading to membrane fusion. The attractive van der Waals forces play a negligible role in membrane fusion. Thus, fusion is a result of the hydrophobic attractions between internal hydrocarbon chain groups that are exposed to the normally inaccessible aqueous environment. Fusion is observed to start at points on the membranes where the membrane stresses are either the weakest or the strongest.
Applications
Interbilayer forces play a key role in mediating membrane fusion, which has extremely important biomedical applications.- The most important application of membrane fusion is in the production of hybridomas which are cells that arise as a result of the fusion of antibodyAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-secreting and immortal B-cells. Hybridomas are used in the industry for the production of monoclonal antibodiesMonoclonal antibodiesMonoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
.
- Membrane fusion also has a major role in cancer immunotherapyCancer immunotherapyCancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease...
. Currently, one of the approaches in cancer immunotherapy involves vaccinationVaccinationVaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...
of dendritic cells which express a specific tumorTumorA tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
on their membranes. Instead, the hybrid cells obtained from the fusion of dendritic cells with tumor cells can be used. These hybrids would help in the expression of a range of tumor-associated antigens on their membranes.
- Understanding membrane fusion better can also lead to improvements in gene therapyGene therapyGene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
.
See also
- Lipid bilayers
- Hydrophobic effectHydrophobic effectThe hydrophobic effect is the observed tendency of nonpolar substances to aggregate in aqueous solution and exclude water molecules. The name, literally meaning "water-fearing," describes the segregation and apparent repulsion between water and nonpolar substances...
- Surface forces apparatusSurface forces apparatusThe surface force apparatus is a scientific instrument and technique pioneered by D. Tabor, R.H.S. Winterton, J.N. Israelachvili in the early 1970s at Cambridge University...
- Cell membraneCell membraneThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
- HydrateHydrateHydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water. The chemical state of the water varies widely between hydrates, some of which were so labeled before their chemical structure was understood....