Molten Globules

Abstract

The term molten globule refers to a compact denatured state: Both experimental and theoretical descriptions have been proposed. Recent reviews include those of Ptitsyn (1, 2), Kuwajima (3), Dill and Shortle (4), Christensen and Pain (5), and Baldwin (6). There is considerable controversy regarding the details of exactly what constitutes a molten globule. This is occasioned in part by apparently contradictory experimental evidence for, on the one hand, an unstructured collapsed species with a hydrophobic core, and on the other a structured species with fixed specific secondary structure (summarized by Baldwin [6]). Baldwin proposed that the solution to this apparent paradox was the existence of two classes of molten globule, the “true” molten globule, corresponding to the structured form, and a “collapsed unfolded form” for the unstructured species (6). As discussed below there is now clear experimental data to indicate that two classes of compact denatured states of proteins exist: compact intermediates, in the thermodynamic sense (i.e., a minimum in the free energy profile for the reaction), which may be considered to be molten globules, and compact forms of the unfolded state (7). It is important to note that it is often experimentally difficult to distinguish between the two forms, especially by spectral methods. Theoretical models for the existence of two classes of denatured states have been presented by Dill and coworkers (8), by Ptitsyn (1, 2), and by Finklestein and Shakhnovich (9). Transient molten globule-like intermediates have also been observed during the refolding of unfolded proteins (10, 11). For the purpose of this chapter the major focus will be on equilibrium molten globules, rather than “kinetic” ones.