Table 1.

Timeline of major concepts in protein structure-function relationships.

1884: Fischer's lock and key model.

1924: First insights about protein globularity.

1930: First x-ray interpretation of fibrillar nature of keratin.

1936: Native state definition by Minsky & Pauling.

1950: Karush proposed a native state with several conformers.

1958: Koshland's induced-fit model.

1960: Structure of hemoglobin

1965: Monod's pre-equilibrium model.

1976: Fold types are classified based on secondary structure content and organization.

1978: Methods to detect internal repetitions in proteins.

1987: Folding funnel hypothesis predicts that native state is its free energy minimum

1994: First characterized knotted protein.

1995: First structural evidence of circular proteins.

1997: Phase transition proteins are associated with human diseases.

1998: Conformational movements in ordered proteins start to be classified.

1999: Intrinsically disordered proteins start to shift the structure-function paradigm.

2006: First characterization of functional amyloid in mammals.

2007: Shortest protein (11 amino acids) characterized.

2015: Notion of “dark” proteins.

2018: Fold-switching proteins are proposed to be widespread