Protein folding: how, why, and beyond

Identifying the series of molecular events that take place when a protein molecule folds or unfolds has confounded and delighted researchers alike while challenging the limits of experimental approaches and the applicability of theoretical models and simulations. This chapter discusses the vast conformational space accessible to a protein chain, the diversity of weak noncovalent interactions it makes, the role of solvent compensating energetic-entropic terms, and the cellular environment, all of which weave an intricate fabric of complexity during the folding of a protein. Emphasis is placed on how generating conformational landscapes in a quantitative fashion can provide an unparalleled view of competing substates, which can either aid in or hinder folding, thus playing a role in function and disease. The role and effect of mutations, the drivers of evolution, are discussed in detail along with the current high pedestal of disordered proteins that has overturned the conventional structure-function paradigm.