Editing Molten globule

{{Short description|Partially-folded protein state}}

In [[molecular biology]], the term '''molten globule''' ('''MG''') refers to [[protein]] states that are more or less compact (hence the "globule"), but are lacking the specific tight packing of [[amino acid residues]] which creates the [[Solid-state physics|solid state]]-like [[Protein tertiary structure|tertiary structure]] of completely folded proteins (hence the "molten"). 

Protein folding is navigated by a dynamic interplay of secondary and tertiary interactions. Two extreme folding pathway models have been formulated. In the first - the framework model - rapidly formed secondary structure elements assemble into a native tertiary structure.<ref>{{Cite journal |last1=Kim |first1=P. S. |last2=Baldwin |first2=R. L. |date=1990 |title=Intermediates in the folding reactions of small proteins. |journal=Annu. Rev. Biochem. |volume=59 |pages=631–660|doi=10.1146/annurev.bi.59.070190.003215 |pmid=2197986 }}</ref> In the second - the hydrophobic collapse model - the formation of a loosely packed tertiary structure precedes secondary structure acquisition.<ref>{{Cite journal |last=Dill |first=K. A. |date=1985 |title=Theory for the folding and stability of globular proteins. |journal=Biochemistry |volume=24 |issue=6 |pages=1501–1509|doi=10.1021/bi00327a032 }}</ref> A nucleation-condensation mechanism involving concomitant formation of short and long-range interactions combines features of both extreme models and thereby represents a unifying mechanism of protein folding.<ref>{{Cite journal |last1=Daggett |first1=V. |last2=Fersht |first2=A. R. |date=2003 |title=Is there a unifying mechanism for protein folding? |journal=Trends Biochem. Sci. |volume=28 |issue=1 |pages=18–25|doi=10.1016/S0968-0004(02)00012-9 |pmid=12517448 }}</ref>

During folding, proteins span a continuum of conformers starting from the denature and ending at the native state. Although often considered a statistical random coil, the denatured state can retain residual structure that mediates (re)folding.<ref>{{Cite journal |last1=Dill |first1=K. A. |last2=Shortle |first2=D. |title=Denatured states of proteins. |journal=Annu. Rev. Biochem. |date=1991 |volume=60 |pages=795–825|doi=10.1146/annurev.bi.60.070191.004051 |pmid=1883209 }}</ref> For instance, staphylococcal nuclease retains native-like topology in 8M urea,<ref>{{Cite journal |last1=Shortle |first1=D. |last2=Ackerman |first2=M. S. |date=2001 |title=Persistence of native-like topology in a denatured protein in 8M urea. |journal=Science |volume=293 |issue=5529 |pages=487–489|doi=10.1126/science.1060438 |pmid=11463915 }}</ref> while nonnative lysozyme contains hydrophobic clusters held together by long-range interactions.<ref>{{Cite journal |last1=Klein-Seetharaman |first1=J. |last2=Oikawa |first2=M. |last3=Grimshaw |first3=S. B. |last4=Wirmer |first4=J. |last5=Duchard |first5=E. |last6=Ueda |first6=T. |last7=Imoto |first7=T. |last8=Smith |first8=L. J. |last9=Dobson |first9=C. M. |last10=Schwalbe |first10=H. |date=2002 |title=Long-range interactions within a nonnative protein. |journal=Science |volume=295 |issue=5560 |pages=1719–1722|doi=10.1126/science.1067680 |pmid=11872841 |bibcode=2002Sci...295.1719K }}</ref> By rapidly adjusting experimental conditions to favor native structure formation, relatively compact protein folding intermediates have been observed.<ref>{{Cite journal |last1=Cecconi |first1=C. |last2=Shank |first2=E. A. |last3=Bustamante |first3=C. |last4=Marqusee |first4=S. |date=2005 |title=Direct observation of the three-state folding of a single protein molecule. |journal=Science |volume=309 |issue=262 |pages=2057–2060|doi=10.1126/science.1116702 |pmid=16179479 |bibcode=2005Sci...309.2057C }}</ref> These kinetic intermediates - coined molten globules<ref>{{Cite journal |last=Ptitsyn |first=O. |date=1995 |title=Molten globule and protein folding. |journal=Adv. Protein Chem. |series=Advances in Protein Chemistry |volume=47 |pages=83–229|doi=10.1016/S0065-3233(08)60546-X |pmid=8561052 |isbn=978-0-12-034247-1 }}</ref> - exhibit native-like secondary structure and fluctuating tertiary structure.  

The molten globule state can also be thermodynamically accessed under mildly denaturing conditions. It was found, for example, 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 state|native]] and the [[denatured state]], demonstrating for the first time the existence of a third equilibrium (i.e., intermediate) state.

The term "molten globule" may be used to describe various types of partially-folded protein states<ref>{{cite journal|author=Baldwin RL|author2=Rose GD|title=Molten globules, entropy-driven conformational change and protein folding.|journal=Curr Opin Struct Biol|date=2013|volume=23|issue=1|pages=4–10|doi=10.1016/j.sbi.2012.11.004|pmid=23237704}}</ref> found in slightly denaturing conditions such as low pH (generally pH = 2), mild denaturant, or high [[temperature]]. Molten globules are collapsed and generally have some native-like secondary structure but a dynamic tertiary structure as seen by far-UV and near-UV [[circular dichroism]] (CD) [[spectroscopy]], respectively.  These traits are similar to those observed in the transient intermediate states found during the folding of certain proteins, especially [[globular protein]]s that undergo [[hydrophobic collapse]], 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]] 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]]s that characterize the native state (<chem>N</chem>) of a protein. The transition from a denatured (<chem>U</chem>) state to a molten globule may be a two state process

: <chem>U <-> MG</chem>

Or it may be a continuous transition, with no [[cooperative binding|cooperativity]] and no apparent "switch" from one form to the other. The folding of some proteins can be modeled as a three-state [[kinetic energy|kinetic]] process:

: <chem>U <-> MG <-> N</chem>

One of the difficulties in ''[[De novo synthesis|de novo]]'' [[protein design]] 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]] algorithm; however, attempts to design proteins of novel folds have difficulty using this method due to an absence of plausible backbone models.

==See also==
*[[Intrinsically disordered proteins]]
*[[Folding funnel]]
*[[Fuzzy complex]]
*[[Hydrophobic collapse]]
*[[Biomolecular condensate]]

== References ==
{{Reflist}}
* {{cite journal |doi=10.1016/0014-5793(83)80010-6 |vauthors=Ohgushi M, Wada A |year=1983 |title='Molten-globule state': a compact form of globular proteins with mobile side-chains.|journal=FEBS Lett.|volume=164 |issue=1 |pages=21–24 |pmid=6317443|s2cid=41232316 |doi-access=free |bibcode=1983FEBSL.164...21O }}
* {{cite journal |vauthors=Kuroda Y, Kidokoro S, Wada A |year=1992 |title=Thermodynamic characterization of cytochrome c at low pH. Observation of the molten globule state and of the cold denaturation process.|journal=J Mol Biol |volume=223 |issue=4 |pages=1139–53 |pmid=1311387 |doi=10.1016/0022-2836(92)90265-l}}
* {{cite book |vauthors=Bieri O, Kiefhaber T |date=2000-12-15 |chapter=Kinetic models in protein folding |title=Mechanisms in Protein Folding |edition=2nd |editor=RH Pain |publisher=Oxford University Press |location=Oxford, UK |isbn=0-19-963788-1}}
* {{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 |bibcode=1998PNAS...95.1490P }}
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

[[Category:Protein structure]]
[[Category:Proteomics]]
[[Category:Proteins by structure]]