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. For cytochrome c and some other proteins, it has been shown that the molten globule state is a "thermodynamic state" clearly different both from the native

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...

 and the denatured state, demonstrating for the first time the existence of a third equilibirum (i.e., intermediate)state.

The term "molten globule" is presently extended to include various types of partially folded 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...

 states found in mildly denaturing

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...

 conditions such as low pH

PH

In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

 (generally pH = 2), mild denaturant, or high temperature

Temperature

Temperature is a physical property of matter that quantitatively expresses the common notions of hot and cold. Objects of low temperature are cold, while various degrees of higher temperatures are referred to as warm or hot...

. Molten globules are collapsed and generally have some native-like 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...

 but a dynamic 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:...

 as seen by far and near circular dichroism

Circular dichroism

Circular dichroism refers to the differential absorption of left and right circularly polarized light. This phenomenon was discovered by Jean-Baptiste Biot, Augustin Fresnel, and Aimé Cotton in the first half of the 19th century. It is exhibited in the absorption bands of optically active chiral...

 (CD) spectroscopy

Spectroscopy

Spectroscopy is the study of the interaction between matter and radiated energy. Historically, spectroscopy originated through the study of visible light dispersed according to its wavelength, e.g., by a prism. Later the concept was expanded greatly to comprise any interaction with radiative...

, respectively. These traits are similar to those observed in the transient intermediate states found during the folding of certain proteins, especially 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 that undergo 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...

, and therefore the term "molten globule" is also used to refer to certain 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....

 intermediates corresponding to the narrowing region 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...

 higher in energy than the 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...

 but lower than 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. The molten globule ensembles sampled during protein folding and unfolding are thought to be roughly similar.

The MG structure is believed to lack the close packing of 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 that characterize the 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...

 (N) of a protein. The transition from a denatured (U) state to a molten globule may be a two state process

U ↔ MG

Or it may be a continuous transition, with no cooperativity

Cooperative binding

In biochemistry, a macromolecule exhibits cooperative binding if its affinity for its ligand changes with the amount of ligand already bound.Cooperative binding is a special case of allostery. Cooperative binding requires that the macromolecule have more than one binding site, since cooperativity...

 and no apparent "switch" from one form to the other. The folding of some proteins can be modeled as a three-state kinetic

Kinetic energy

The kinetic energy of an object is the energy which it possesses due to its motion.It is defined as the work needed to accelerate a body of a given mass from rest to its stated velocity. Having gained this energy during its acceleration, the body maintains this kinetic energy unless its speed changes...

 process:

U ↔ MG ↔ N

One of the difficulties in de novo protein design

Protein design

Protein design is the design of new protein molecules, either from scratch or by making calculated variations on a known structure. The use of rational design techniques for proteins is a major aspect of protein engineering....

 is achieving the side chain packing needed to create a stable native state rather than an ensemble of molten globules. Given a desired backbone conformation, side chain packing can be designed using variations of the dead-end elimination

Dead-end elimination

The dead-end elimination algorithm ' is a method for minimizing a function over a discrete set of independent variables. The basic idea is to identify "dead ends", i.e., "bad" combinations of variables that cannot possibly yield the global minimum and to refrain from searching such combinations...

algorithm; however, attempts to design proteins of novel folds have difficulty using this method due to an absence of plausible backbone models.