Molecular Chaperones

In most cases proteins fold spontaneously under physiological conditions and do not require any external assistance. This has become evident since the experiments on ribonuclease A conducted by Anfinsen in ‘50s and ‘60s. The list of such “successful” folders has grown since and now includes many two-state proteins catalogued in Folding & Design 3, R81. These proteins fold rapidly and reliably to their native states without being trapped in intermediates. Yet protein folding is a very delicate process, which occurs in a narrow window of external conditions. As a result there are many factors, which may potentially impede folding by increasing the roughness of energy landscape of proteins. Due to particular sequence composition or adverse change in external condition (cellular stress), folding funnel may have significant energy ‘ripples” separated by deep minima, which are distinctive from the native state. As a result proteins may be trapped in non-native misfolded structures, which can be quite stable, because they have low energy comparable with the native one. The problem is further aggravated by the fact that in such misfolded conformations proteins often have patches of hydrophobic residues exposed to solvent. Because cellular environment is crowded with other molecules, misfolded proteins may interact with those and irreversibly aggregate into large assemblies. Aggregation often leads to dreadful consequences for cells and organism as a whole. Alzheimer’s, Parkinson’s, “mad cow” diseases are just few examples of deadly protein aggregation.