Editorial Hot Topic: Protein Folding & Misfolding (Guest Editor: Carlos Henrique I. Ramos)]

The three-dimensional structure of a protein depends on its amino acid sequence, as do the stability and the folding mechanism. The first milestones in the study of protein folding took place at the beginning of the 20th century: in 1911, Chick and Martin (J. Physiol. 43:1) showed that proteins can be denaturated; in 1931, Wu (Chin. Physiol. 1:219) showed that the process of denaturation involves unfolding; and in 1931, Anson and Mirsky (Phys. Chem. 35:185) showed that the process of unfolding can be reverted. Almost a century later, the convergence of theoretical and experimental work has started to unify the current view of the folding process. This special issue on Protein Folding & Misfolding deals with the biological and physical aspects of this important process. The leading review in this issue, written by Ramos and Ferreira, gives a general view of the field throughout the description of the intermediates, the transition states, the models on protein folding, the biotechnological challenges caused by protein misfolding and aggregation, and the dreadful consequences that misfolding and aggregation can have on conformational diseases. The review by Pereira de Araújo, centered on the use of minimalist models to understand the thermodynamics of cooperative protein folding, addresses the importance of the use of computational methods to understand protein folding. Jamin gives an overview on the folding process of one of the best studied models for protein folding, apomyoglobin, with special attention to the characterization of its folding kinetics. The reviews by Spyracopolous, on the use of nuclear magnetic resonance spectroscopy to determine thermodynamic parameters of proteins, and by Correa and Farah, on the use of 5-hydroxytryptophan as a fluorescence probe to monitor structural properties of proteins, emphasize the importance of spectroscopic techniques as tools for the investigation of folding and stability. Differently from well-behaved proteins that are usually stable at several different conditions, some proteins have a strong tendency to aggregate or to form fibrils, which have medical relevance because these proteins are associated with conformational diseases. In her review, Foguel neatly presents the interpretation of current results in the formation of fibrils by transthyretin using high hydrostatic pressure to investigate the aggregate states of this protein. Cordeiro and Silva center their review on the possible causes of the conversion of the prion protein into its infectious form, pointing out the nucleotide interactions as active components in this reaction. Although we find protein folding very complex, it takes place continually inside cells, partly because of the action of chaperones, proteins involved in a complex machinery in keeping other proteins in their folded states. Chaperones are the theme of the review by Borges and Ramos that summarizes the recent findings in this field. Throughout the articles in this special issue, we see that the final picture emerging from protein folding studies is that this process is governed by simplistic principles. While stability depends more on specific inter-atomic contacts between amino acid residues, the mechanism of folding appears to depend more on the global geometry, or topology, of the native structure. The determination of the protein folding principles is opening a new era in which the structural prediction and design of novel protein structures from the corresponding amino acid sequences are becoming possible. However, considerable work still needs to be done so that we can fully understand how the amino acid sequence encodes the characteristics related to the shape of the folding funnel and to the overall topology of the native protein.