STRUCTURAL ENERGETICS OF THE MOLTEN GLOBULE STATE

Certain partly ordered protein conformations, commonly called ''molten globule states,'' are widely believed to represent protein folding in termediates. Recent structural studies of molten globule states of dif ferent proteins have revealed features which appear to be general in s cope. The emerging consensus is that these partly ordered forms exhibi t a high content of secondary structure, considerable compactness, non specific tertiary structure, and significant structural flexibility. T hese characteristics may be used to define a general state of protein folding called ''the molten globule state,'' which is structurally and thermodynamically distinct from both the native state and the denatur ed state. Despite extensive knowledge of structural features of a few molten globule states, a cogent thermodynamic argument for their stabi lity has not yet been advanced. The prevailing opinion of the last dec ade was that there is little or no enthalpy difference or heat capacit y difference between the molten globule state and the unfolded state. This view, however, appears to be at variance with the existing databa se of protein structural energetics and with recent estimates of the e nergetics of denaturation of alpha-lactalbumin, cytochrome c, apomyogl obin, and T4 lysozyme. We discuss these four proteins at length. The r esults of structural studies, together with the existing thermodynamic values for fundamental interactions in proteins, provide the foundati on for a structural thermodynamic framework which can account for the observed behaviour of molten globule states. Within this framework, we analyze the physical basis for both the high stability of several mol ten globule states and the low probability of other potential folding intermediates. Additionally, we consider, in terms of reduced enthalpy changes and disrupted cooperative interactions, the thermodynamic bas is for the apparent absence of a thermally induced, cooperative unfold ing transition for some molten globule states.