Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions

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.

Solution of Levinthal’s Paradox and a Physical Theory of Protein Folding Times

“…Fortunately, this can be done rather readily, because a recent review published in Biomolecules [6] outlines progress in the field of in vivo protein folding. (See also References [7,8]. ) We can begin by comparing protein structure formation times in vivo and in vitro.…”

“…Anfinsen proposed a "thermodynamic hypothesis", assuming that the native structure is the global free energy minimum at physiological conditions [2] because all chains of a given protein fold into the same native structure in diverse processes: At biosynthesis, after renaturation, or even after chemical synthesis [26]. (We consider only conformations of separate monomeric protein chains, and do not consider aggregated structures considered in [7]).…”

Trehalose Effect on The Aggregation of Model Proteins into Amyloid Fibrils

“…Several advances are made to understand and get detailed insight into the structural basis and mechanism of amyloid fibrils formation, cytotoxicity and therapeutic approaches to combat them [21][22][23][24][25][26][27][28]. In particular, when considering results collected on trehalose in the context of protein fibrillation, attention has to be paid also to the external environment characterized by a defined ionic strength and subjected to a particular redistribution of water molecules in proximity of protein surfaces.…”

Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

“…Intrinsically-disordered proteins and regions are complicated, as they do not have unique and simple characteristics. Hence, IDPs represent complete disordered proteins that stay disordered, but they can also adopt one conformation when they bind to their ligands or partners [ 66 , 67 ] or participate in multiple systems [ 68 ], they are essential to functions [ 69 , 70 ], drug design [ 71 ], and protein design [ 72 ].…”