Hydrophobic collapse
Encyclopedia
Hydrophobic collapse is a hypothesized event that occurs during the folding
process of globular protein
s, suggested on the basis of the observation that proteins' native state
s often contain a hydrophobic core of nonpolar amino acid
side chain
s (interspersed with charged side chains that are neutralized by salt bridges) in the protein's interior, leaving most of the polar or charged residues on the solvent
-exposed protein surface. The energetic stabilization conferred on the protein by the sequestration of the hydrophobic side chains from the surrounding water is thought to stabilize folding intermediates. The hypothesis generally posits that hydrophobic collapse is relatively early event in the folding pathway, occurring before the formation of many secondary structure
s and native contact
s present in the fully folded tertiary structure
. The collapsed intermediate is also referred to as a molten globule
and corresponds to a partially folded state whose energy is lower than that of the denatured state
but higher than that of the native state - that is, within the energy well of the folding funnel
but not yet close to the energy minimum.
Partial hydrophobic collapse is an experimentally accepted model for the folding kinetics
of many globular proteins, such as myoglobin
, alpha-lactalbumin
, barstar
, and staphylococcal
nuclease
. However, because experimental evidence of early folding events is difficult to obtain, hydrophobic collapse is often studied in silico via molecular dynamics
and Monte Carlo
simulations of the folding process. Globular proteins that are thought to fold by hydrophobic collapse are particularly amenable to complementary computational and experimental study using phi value analysis
.
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....
process of globular protein
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...
s, suggested on the basis of the observation that proteins' 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...
s often contain a hydrophobic core of nonpolar 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 (interspersed with charged side chains that are neutralized by salt bridges) in the protein's interior, leaving most of the polar or charged residues on the solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
-exposed protein surface. The energetic stabilization conferred on the protein by the sequestration of the hydrophobic side chains from the surrounding water is thought to stabilize folding intermediates. The hypothesis generally posits that hydrophobic collapse is relatively early event in the folding pathway, occurring before the formation of many secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
s and 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 present in the fully folded 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 collapsed intermediate is also referred to as a 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...
and corresponds to a partially folded state whose energy is lower than that of the denatured state
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...
but higher than that of the native state - that is, within the energy well of the folding funnel
Folding funnel
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...
but not yet close to the energy minimum.
Partial hydrophobic collapse is an experimentally accepted model for the folding kinetics
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....
of many globular proteins, such as myoglobin
Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. The only time myoglobin is found in the...
, alpha-lactalbumin
Alpha-lactalbumin
Lactalbumin, alpha-, also known as LALBA, is a protein that in humans is encoded by the LALBA gene.- Function :α-Lactalbumin is an important whey protein in cow's milk , and is also present in the milk of many other mammalian species...
, barstar
Barstar
Barstar is a small protein synthesized by the bacterium Bacillus amyloliquefaciens. Its function is to inhibit the ribonuclease activity of its binding partner barnase, with which it forms an extraordinarily tightly bound complex within the cell until barnase is secreted. Expression of barstar is...
, and staphylococcal
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....
nuclease
Nuclease
A nuclease is an enzyme capable of cleaving the phosphodiester bonds between the nucleotide subunits of nucleic acids. Older publications may use terms such as "polynucleotidase" or "nucleodepolymerase"....
. However, because experimental evidence of early folding events is difficult to obtain, hydrophobic collapse is often studied in silico via molecular dynamics
Molecular dynamics
Molecular dynamics is a computer simulation of physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a period of time, giving a view of the motion of the atoms...
and Monte Carlo
Monte Carlo method
Monte Carlo methods are a class of computational algorithms that rely on repeated random sampling to compute their results. Monte Carlo methods are often used in computer simulations of physical and mathematical systems...
simulations of the folding process. Globular proteins that are thought to fold by hydrophobic collapse are particularly amenable to complementary computational and experimental study using phi value analysis
Phi value analysis
Phi value analysis is an experimental protein engineering method used to study the structure of the folding transition state in small protein domains that fold in a two-state manner. Since the folding transition state is by definition a transient and partially unstructured state, its structure is...
.