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A molten globule (MG) is a stable, partially folded protein state found in mildly 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 and near 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 proteins 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 chains 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 and no apparent "switch" from one form to the other. The folding of some proteins can be modeled as a three-state kinetic process:

U ↔ MG ↔ N

One of the difficulties in 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.

• Bieri O, Kiefhaber T. (2000). Kinetic models in protein folding. In Mechanisms in Protein Folding 2nd ed. Ed. RH Pain. Oxford University Press: Oxford, UK.
• Pande VS, Rokhsar DS (1998) Is the molten globule a third phase of proteins? Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1490-4 Entrez PubMed 9465042