Searching for “downhill scenarios” in protein folding

Abstract

The genome project, with the discovery of thousands of new protein sequences every year, has created a revolution in protein physics, chemistry, and biology. This has led to a renewed and very much expanded interest in the protein folding problem, particularly among biophysical scientists. There are two parts to this problem. The first is predicting the three-dimensional structure of a protein from its amino acid sequence, often referred to as cracking the second half of the genetic code. The second, which is the subject of this Commentary, is to understand how proteins fold. This problem has recently taken on additional importance, as more and more human diseases, such as Alzheimer’s and Parkinson’s diseases, are believed to be caused by aggregation of misfolded proteins (1). There is, moreover, the intriguing possibility that evolution preserves sequences that not only form structures that adequately perform a specific biological function but also those that avoid misfolded states and fold sufficiently quickly to avoid aggregation. That is, minimizing nonnative interactions and maintaining sufficient folding speed may very well be additional selection pressures in protein evolution (2, 3). The question of how a protein folds can be phrased more precisely as follows: What are the sequences of structural changes that occur in a polypeptide as it finds its way from the myriad of possible structures in the denatured state to the final, unique native structure? How many different folding routes exist and what are their relative probabilities? The article by Sabelko et al. in this issue of the Proceedings (4) represents a significant advance toward answering these questions. These investigators observe a time course for folding that does not have the functional form corresponding to a single exponential or a sum of a few exponentials, as has been observed previously in studies …