Proteins often fold quite rapidly (< 1s) because the energy bias on a funnel-shaped landscape steers unfolded peptides toward native conformations [5,134]. However, proteins do not fold by randomly searching a large number of nearly degenerate configurations (Levinthal's paradox) ; instead, an ensemble of unfolded molecules must traverse a complicated energy landscape to reach a thermodynamically stable structure [1,5,29,134]. The configurational entropy of a polypeptide, represented by the lateral dimension on a folding energy landscape, is minimized at the native conformation. The high energy portion of the conformational landscape represents a heterogeneous ensemble of unfolded polypeptides; partially folded conformations appear as local minima on this energy surface and misfolded structures can be in deep energy wells that are separated from the native minimum (Figure 12). In order to map this complex energy landscape, it is necessary to probe structural features of the polypeptide ensemble as it evolves to the native state.
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