Experimental investigation of sidechain interactions in early folding intermediates

Kinetic studies of folding sometimes reveal very rapid spectroscopic changes that may indicate the population of intermediates, but it is difficult to elucidate in detail the nature of the interactions involved. In this review, we focus on one important aspect of this problem: how to probe the nature and extent of clustering of hydrophobic sidechains. As the information obtainable from different experimental approaches is outlined, it becomes clear that a combination of methods is likely to be necessary to build up a reasonable picture of early folding events.