How does solvation in the cell affect protein folding and binding?

•Studies in live cells reveal complex interactions between proteins and intracellular solvent.•Small solutes and water play a key role in mediating solvation effects.•Protein interaction with the cellular environment is described using transfer free-energies.•Evolutionary pressure acts on weak interactions, leading to quinary interactions.•Weak but correlated interactions can produce large physiological effects.

The cellular environment is highly diverse and capable of rapid changes in solute composition and concentrations. Decades of protein studies have highlighted their sensitivity to solute environment, yet these studies were rarely performed in situ. Recently, new techniques capable of monitoring proteins in their natural context within a live cell have emerged. A recurring theme of these investigations is the importance of the often-neglected cellular solvation environment to protein function. An emerging consensus is that protein processes in the cell are affected by a combination of steric and non-steric interactions with this solution. Here we explain how protein surface area and volume changes control these two interaction types, and give recent examples that highlight how even mild environmental changes can alter cellular processes.

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