Editorial: Special Issue on Protein Folding and Aggregation

Abstract

The theme of protein folding is increasingly becoming a hot topic for the attention of not only biochemists, biophysicists, biotechnologists, cell and molecular biologists but also of researchers in the fields of molecular evolution and molecular medicine. Actually, protein folding has progressively revealed multi-faceted aspects linking it to two other, strictly related aspects, protein misfolding and aggregation that are being shown to be at the basis of many physiological and pathological processes. In the past 15-20 years, all these themes have undergone profound changes of paradigms. The energy landscape theory of protein folding has provided a solid theoretical basis to interpret old experimental data and to design new experimental approaches also taking benefit of newly introduced spectroscopic and fluorescence methods. It has also exploited the single-mutant approach first introduced by Alan Fesht to assess the contribution of each single residue in the overall folding process. Presently, we can consider with confidence the possibility that in a near future we will be able to decrypt the folding code encrypted in the amino acid sequence of each polypeptide chain enabling us to propose with good approximation a three-dimensional structure from any given one-dimensional string of amino acid residues under specific environmental conditions. Protein misfolding is increasingly seen as much more than a mere defect of protein folding. Rather, presently it is considered the other side of the coin of protein folding. The protein conformational states available to a polypeptide chain go well beyond the natively folded, biologically active, form. Aberrantly folded, or misfolded, states in dynamic equilibrium with the correctly folded conformation appear continuously in the population of a protein's molecules. Accordingly, a protein solution can be considered a collection of different conformational states undergoing very rapid interchange where the native state is the most highly populated, which occupies a minimal energy state. This is the theoretical basis to understand the effects of structural (amino acid substitutions) or environmental (pH, temperature, chemical modification, presence of surfaces or stabilising ligands, protein over-expression) perturbations affecting the folded-misfolded equilibrium with the resulting quantitative modification of the different structures of the polypeptide chain populated at the equilibrium. The review by Paavo Kinnunen strengthens the importance of surfaces in affecting the behaviour of polypeptide chains making them more or less susceptible to misfolding/unfolding. This is a very important point, considering that the intracellular milieu is dramatically crowded by macromolecules and membranes and hence of surfaces with different …