molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...

, the term molten globule (MG) refers to

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

states that are more or less compact (hence the "globule"), but are lacking the specific tight packing of

amino acid residues Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer may ...

which creates the solid state-like

tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may int ...

of completely

folded proteins Protein folding is the physical process by which a protein chain is Translation (biology), translated to its native protein tertiary structure, three-dimensional structure, typically a "folded" Protein structure, conformation by which the prote ...

. It was found, for example, in

cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

, which conserves a native-like

secondary structure Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

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 In thermodynamics, a thermodynamic state of a system is its condition at a specific time; that is, fully identified by values of a suitable set of parameters known as state variables, state parameters or thermodynamic variables. Once such a set o ...

" clearly different both from the

native Native may refer to: People * Jus soli, citizenship by right of birth * Indigenous peoples, peoples with a set of specific rights based on their historical ties to a particular territory ** Native Americans (disambiguation) In arts and entert ...

and the denatured state, demonstrating for the first time the existence of a third equilibirum (i.e., intermediate) state. The term "molten globule" may be used to describe various types of partially-folded protein states found in slightly denaturing conditions such as low pH (generally pH = 2), mild denaturant, or high

temperature Temperature is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measured with a thermometer. Thermometers are calibrated in various temperature scales that historically have relied o ...

. Molten globules are collapsed and generally have some native-like secondary structure but a dynamic tertiary structure as seen by far and near circular dichroism (CD)

spectroscopy Spectroscopy is the field of study that measures and interprets the electromagnetic spectra that result from the interaction between electromagnetic radiation and matter as a function of the wavelength or frequency of the radiation. Matter wa ...

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

globular protein In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (formi ...

s that undergo

hydrophobic collapse Hydrophobic collapse is a proposed process for the production of the Protein structure, 3-D conformation adopted by Peptide, polypeptides and other molecules in polar solvents. The theory states that the nascent polypeptide forms initial Protein se ...

, and therefore the term "molten globule" is also used to refer to certain protein folding intermediates corresponding to the narrowing region of the

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 but lower than the denatured 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

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 the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a l ...

s that characterize the native state (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 Cooperativity is a phenomenon displayed by systems involving identical or near-identical elements, which act dependently of each other, relative to a hypothetical standard non-interacting system in which the individual elements are acting indepen ...

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

kinetic Kinetic (Ancient Greek: κίνησις “kinesis”, movement or to move) may refer to: * Kinetic theory of gases, Kinetic theory, describing a gas as particles in random motion * Kinetic energy, the energy of an object that it possesses due to i ...

process: : U <-> MG <-> N One of the difficulties in '' de novo''

protein design Protein design is the rational design of new protein molecules to design novel activity, behavior, or purpose, and to advance basic understanding of protein function. Proteins can be designed from scratch (''de novo'' design) or by making calcula ...

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 The dead-end elimination algorithm (DEE) is a method for optimization (mathematics), minimizing a Function (mathematics), function over a discrete set of independent variables. The basic idea is to identify "dead ends", i.e., combinations of vari ...

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

References

* * * * {{cite journal , doi=10.1073/pnas.95.4.1490 , vauthors=Pande VS, Rokhsar DS , year=1998 , title=Is the molten globule a third phase of proteins? , journal=Proc Natl Acad Sci USA , volume=95 , issue=4 , pages=1490–1494 , pmid=9465042 , pmc=19058, doi-access=free Jaremko, M., Jaremko, L., Kim, H.-Y., Cho, M.-K., Schwieters, C. D., Giller, K., Becker, S., Zweckstetter, M. (2013) Cold denaturation of a protein dimer monitored at atomic resolution, Nat. Chem. Biol. 9, 264-270 Protein structure Proteomics Proteins by structure

See also

References