A look back at the molten globule state of proteins: thermodynamic aspects

Abstract

Interest in protein folding intermediates lies in their significance to protein folding pathways. The molten globule (MG) state is one such intermediate lying on the kinetic (and sometimes thermodynamic) pathway between native and unfolded states. Development of our qualitative and quantitative understanding of the MG state can provide deeper insight into the folding pathways and hence potentially facilitate solution of the protein folding problem. An extensive look at literature suggests that most studies into protein MG states have been largely qualitative. Attempts to obtain quantitative insights into MG states have involved application of high-sensitivity calorimetry (differential scanning calorimetry and isothermal titration calorimetry). This review addresses the progress made in this direction by discussing the knowledge gained to date, along with the future promise of calorimetry, in providing quantitative information on the structural features of MG states. Particular attention is paid to the question of whether such states share common structural features or not. The difference in the nature of the transition from the MG state to the unfolded state, in terms of cooperativity, has also been addressed and discussed.

The C-terminal tail extension of myosin 16 acts as a molten globule, including intrinsically disordered regions, and interacts with the N-terminal ankyrin

“…The β-structure content is increased by ~4%, which could be the result of partial aggregation of the protein at high temperatures. The thermal behavior of Myo16Tail showing low cooperativity detected by CD measurements supports the idea of lacking a stable globular fold and is characteristic of a molten globule-like state (90). In conclusion, CD spectroscopy analysis indicates the presence of both disordered and structured regions in Myo16Tail supporting our conclusions from fluorescence spectroscopic measurements according to which the tail of Myo16 might be in a molten globule-like conformation.…”

Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions

“…The structural properties of a protein molecule in the molten globule are well known, and have been outlined in a number of reviews (e.g., [12,13,79,[103][104][105][106][107][108][109][110][111][112][113][114][115][116][117]). Although the molten globular protein completely lacks a rigid, cooperatively-melting, tertiary structure, or has only a trace of such a structure, i.e., is denatured, it preserves high levels of a native-like, secondary structure [12,13,79,[103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118]. Molten globules are compact (in comparison with the native state, their hydrodynamic radii are increased by less than 15%, which translates into a~50% increase in volume) [12,13,18,21,79,[103][104][105]…”

“…Although the molten globular protein completely lacks a rigid, cooperatively-melting, tertiary structure, or has only a trace of such a structure, i.e., is denatured, it preserves high levels of a native-like, secondary structure [12,13,79,[103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118]. Molten globules are compact (in comparison with the native state, their hydrodynamic radii are increased by less than 15%, which translates into a~50% increase in volume) [12,13,18,21,79,[103][104][105][106][107][108][109][110][111][112][113][114][115][116][117]119] and, as evidenced by small-angle X-ray scattering, have a globular structure, which is usually similar to that of native globular proteins [120][121][122][123][124]. The analysis of the molten globules of severa...…”

Milk Processing Affects Structure, Bioavailability and Immunogenicity of β-lactoglobulin

“…Initially β-lactoglobulin conformational shifts upon heating involve destabilization and partial unfolding of its globular structure to expose histidine, tyrosine, and tryptophan residues to the solvent [ 46 ] and increasing reactivity of the buried thiol group [ 47 ]. These limited and reversible conformational changes are followed by dissociation of intramolecular interactions and occupation of a partially unfolded, so-called molten globule state [ 48 ], reviewed in [ 49 ], which is also populated upon refolding of β-lactoglobulin [ 50 ], yielding exposure of the thiol group and the buried hydrophobic core of the protein [ 51 ]. While initial conformational transitions occur at temperatures as low as 40 °C [ 52 ], fully denatured β-lactoglobulin is only observed at temperatures exceeding 130 °C [ 53 , 54 , 55 ], indicating that the denaturation process of β-lactoglobulin can be described as a multistep mechanism.…”