Introduction

The production of functional proteins requires that polypeptides find a unique conformation in a vast space of incorrect folds [1]. The consequences of failure are severe; misfolded proteins are implicated in a rapidly growing list of debilitating neurodegenerative illnesses that includes Alzheimer's, Parkinson's as well as Creutzfeldt-Jakob diseases [2].

To ensure that proteins reach their native states and avoid potentially toxic aggregates, cells have evolved a complex machinery of molecular chaperones that assists the folding of nascent polypeptides and rescues proteins from stress-induced denaturation [3]. Partially folded polypeptide structures are key intermediates in both the proper assembly of proteins, and in the formation of harmful misfolded structures [4-8]. Characterizing the structures, energetics, and dynamics of these transient species is an essential step in understanding their benign and malignant pathways.

Elucidation of key events in protein folding calls for investigations on time scales that range from picoseconds to minutes (Figure 1). The fastest nuclear motions in proteins, rotations about single bonds, occur on the picosecond time scale [9]. Short segments of helical structure can be formed in nanoseconds [10-12], whereas the large scale, collective motions associated with the development of tertiary structure fall in the microsecond to millisecond range [13-15]. Misfolded structures or traps are frequently encountered in folding processes; escape from these traps (e.g., proline isomerization) can take seconds or even minutes [16,17]. Formation of partially folded structures, the so-called 'burst' intermediates observed during a stopped-flow mixing deadtime, has been the most challenging to study because it occurs on a submillisecond time scale [13,14,18-21]. Identification and characterization of these compact structures are critical in

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