In recent years, better instrumentation and greater computing power have enabled the imaging of elusive biomolecule dynamics in cells, driving many advances in understanding the chemical organization of biological systems. The focus of this Review is on interactions in the cell that affect both biomolecular stability and function and modulate them. The same protein or nucleic acid can behave differently depending on the time in the cell cycle, the location in a specific compartment, or the stresses acting on the cell. We describe in detail the crowding, sticking, and quinary structure in the cell and the current methods to quantify them both in vitro and in vivo. Finally, we discuss protein evolution in the cell in light of current biophysical evidence. We describe the factors that drive protein evolution and shape protein interaction networks. These interactions can significantly affect the free energy, δG, of marginally stable and low-population proteins and, due to epistasis, direct the evolutionary pathways in an organism. We finally conclude by providing an outlook on experiments to come and the possibility of collaborative evolutionary biology and biophysical efforts.
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