No abstract

Proteins, these evolutionarily-edited biological polymers, are able to undergo intramolecular and intermolecular phase transitions. Spontaneous intramolecular phase transitions define the folding of globular proteins, whereas binding-induced, intra- and inter- molecular phase transitions play a crucial role in the functionality of many intrinsically-disordered proteins. On the other hand, intermolecular phase transitions are the behind-the-scenes players in a diverse set of macrosystemic phenomena taking place in protein solutions, such as new phase nucleation in bulk, on the interface, and on the impurities, protein crystallization, protein aggregation, the formation of amyloid fibrils, and intermolecular liquid–liquid or liquid–gel phase transitions associated with the biogenesis of membraneless organelles in the cells. This review is dedicated to the systematic analysis of the phase behavior of protein molecules and their ensembles, and provides a description of the major physical principles governing intramolecular and intermolecular phase transitions in protein solutions.

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“How do proteins fold?” Researchers have been studying different aspects of this question for more than 50 years. The most conceptual aspect of the problem is how protein can find the global free energy minimum in a biologically reasonable time, without exhaustive enumeration of all possible conformations, the so-called “Levinthal’s paradox.” Less conceptual but still critical are aspects about factors defining folding times of particular proteins and about perspectives of machine learning for their prediction. We will discuss in this review the key ideas and discoveries leading to the current understanding of folding kinetics, including the solution of Levinthal’s paradox, as well as the current state of the art in the prediction of protein folding times.