A model of protein folding with multiple native states: Metamorphicity, intrinsic disorderness, and folding upon binding of proteins.

The sequence-structure-function paradigm in biology states that a protein's amino acid sequence determines its unique folded state structure, which in turn dictates its unique biological function. This classic concept has been severely challenged by the discovery of metamorphic and intrinsically disordered proteins (IDPs). Metamorphic proteins can fold into multiple native structures and perform multiple functions. IDPs, on the contrary, remain unstructured under physiological conditions but can fold to a unique structure upon binding to a target protein and show functionality. Here, we present a statistical mechanical model of protein folding with multiple native states and analyze their folding phase diagrams. While recovering the classic sequence-structure-function paradigm for a single native state, our model shows metamorphicity at a lower number of native states. An expansion of the unfolded region in the phase diagram at a higher number of native states, making the unfolded state the stable state under physiological conditions, indicates the emergence of an IDP-like scenario. Folding upon binding scenario of IDPs has also been demonstrated when an energetic bias is introduced for a specific native state. A regaining of the folded region upon biasing, increasing the folding propensity of the system, with folding toward a specific native state, is shown. Therefore, our model is general enough to reproduce the classic sequence-structure-function, metamorphicity, intrinsic disorderness, and folding upon binding scenarios of proteins.