Folding funnel
Encyclopedia
The folding funnel hypothesis is a specific version of the energy landscape
theory of protein folding
, which assumes that a protein
's native state
corresponds to its free energy minimum under the solution conditions usually encountered in cells
. Although energy landscapes may be "rough", with many non-native local minima in which partially folded proteins can become trapped, the folding funnel hypothesis assumes that the native state is a deep free energy
minimum with steep walls, corresponding to a single well-defined tertiary structure
.
The folding funnel hypothesis is closely related to the hydrophobic collapse
hypothesis, under which the driving force for protein folding is the stabilization associated with the sequestration of hydrophobic amino acid
side chain
s in the interior of the folded protein. This allows the water solvent to maximize its entropy, lowering the total free energy. On the side of the protein, free energy is further lowered by favorable energetic contacts: isolation of electrostatically charged side chains on the solvent-accessible protein surface
and neutralization of salt bridge
s within the protein's core. The molten globule
state predicted by the folding funnel theory as an ensemble of folding intermediates thus corresponds to a protein in which hydrophobic collapse has occurred but many native contact
s, or close residue-residue interactions represented in the native state, have yet to form.
In the canonical depiction of the folding funnel, the depth of the well represents the energetic stabilization of the native state versus the denatured
state, and the width of the well represents the conformational entropy
of the system. The surface outside the well is shown as relatively flat to represent the heterogeneity of the random coil
state. The theory's name derives from an analogy between the shape of the well and a physical funnel
, in which dispersed liquid is concentrated into a single narrow area.
Energy landscape
In physics, an energy landscape is a mapping of all possible conformations of a molecular entity, or the spatial positions of interacting molecules in a system, and their corresponding energy levels, typically Gibbs free energy, on a two- or three-dimensional Cartesian coordinate system.In...
theory of protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
, which assumes that a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
's native state
Native state
In biochemistry, the native state of a protein is its operative or functional form. While all protein molecules begin as simple unbranched chains of amino acids, once completed they assume highly specific three-dimensional shapes; that ultimate shape, known as tertiary structure, is the folded...
corresponds to its free energy minimum under the solution conditions usually encountered in cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. Although energy landscapes may be "rough", with many non-native local minima in which partially folded proteins can become trapped, the folding funnel hypothesis assumes that the native state is a deep free energy
Thermodynamic free energy
The thermodynamic free energy is the amount of work that a thermodynamic system can perform. The concept is useful in the thermodynamics of chemical or thermal processes in engineering and science. The free energy is the internal energy of a system less the amount of energy that cannot be used to...
minimum with steep walls, corresponding to a single well-defined tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
.
The folding funnel hypothesis is closely related to the hydrophobic collapse
Hydrophobic collapse
Hydrophobic collapse is a hypothesized event that occurs during the folding process of globular proteins, suggested on the basis of the observation that proteins' native states often contain a hydrophobic core of nonpolar amino acid side chains in the protein's interior, leaving most of the polar...
hypothesis, under which the driving force for protein folding is the stabilization associated with the sequestration of hydrophobic amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
s in the interior of the folded protein. This allows the water solvent to maximize its entropy, lowering the total free energy. On the side of the protein, free energy is further lowered by favorable energetic contacts: isolation of electrostatically charged side chains on the solvent-accessible protein surface
Accessible surface area
The accessible surface area is the surface area of a biomolecule that is accessible to a solvent. The ASA is usually quoted in square ångstrom . ASA was first described by Lee & Richards in 1971 and is sometimes called the Lee-Richards molecular surface...
and neutralization of salt bridge
Salt bridge
A salt bridge, in chemistry, is a laboratory device used to connect the oxidation and reduction half-cells of a galvanic cell , a type of electrochemical cell...
s within the protein's core. The molten globule
Molten globule
The term molten globule was first coined by A. Wada and M Ohgushi in 1983. It was first found in cytochrome c, which conserves a native-like secondary structure content but without the tightly packed protein interior, under low pH and high salt concentration...
state predicted by the folding funnel theory as an ensemble of folding intermediates thus corresponds to a protein in which hydrophobic collapse has occurred but many native contact
Native contact
In protein folding, a native contact is a contact between the side chains of two amino acids that are not neighboring in the amino acid sequence but are spatially close in the protein's native state tertiary structure...
s, or close residue-residue interactions represented in the native state, have yet to form.
In the canonical depiction of the folding funnel, the depth of the well represents the energetic stabilization of the native state versus the denatured
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
state, and the width of the well represents the conformational entropy
Conformational entropy
Conformational entropy is the entropy associated with the physical arrangement of a polymer chain that assumes a compact or globular state in solution. The concept is most commonly applied to biological macromolecules such as proteins and RNA, but can also be used for polysaccharides and other...
of the system. The surface outside the well is shown as relatively flat to represent the heterogeneity of the random coil
Random coil
A random coil is a polymer conformation where the monomer subunits are oriented randomly while still being bonded to adjacent units. It is not one specific shape, but a statistical distribution of shapes for all the chains in a population of macromolecules...
state. The theory's name derives from an analogy between the shape of the well and a physical funnel
Funnel
A funnel is a pipe with a wide, often conical mouth and a narrow stem. It is used to channel liquid or fine-grained substances into containers with a small opening. Without a funnel, spillage would occur....
, in which dispersed liquid is concentrated into a single narrow area.
See also
- Protein structure predictionProtein structure predictionProtein structure prediction is the prediction of the three-dimensional structure of a protein from its amino acid sequence — that is, the prediction of its secondary, tertiary, and quaternary structure from its primary structure. Structure prediction is fundamentally different from the inverse...
- Levinthal paradoxLevinthal paradoxLevinthal's paradox is a thought experiment, also constituting a self-reference in the theory of protein folding. In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the molecule has an astronomical number of possible...
- chaperone — proteins that assist other proteins in folding or unfolding