Effects of External Perturbations on Protein Systems: A Microscopic View

[Image: see text] Protein folding can be viewed as the origami engineering of biology resulting from the long process of evolution. Even decades after its recognition, research efforts worldwide focus on demystifying molecular factors that underlie protein structure–function relationships; this is particularly relevant in the era of proteopathic disease. A complex co-occurrence of different physicochemical factors such as temperature, pressure, solvent, cosolvent, macromolecular crowding, confinement, and mutations that represent realistic biological environments are known to modulate the folding process and protein stability in unique ways. In the current review, we have contextually summarized the substantial efforts in unveiling individual effects of these perturbative factors, with major attention toward bottom-up approaches. Moreover, we briefly present some of the biotechnological applications of the insights derived from these studies over various applications including pharmaceuticals, biofuels, cryopreservation, and novel materials. Finally, we conclude by summarizing the challenges in studying the combined effects of multifactorial perturbations in protein folding and refer to complementary advances in experiment and computational techniques that lend insights to the emergent challenges.