A model of protein folding with multiple native states:Metamorphicity, Intrinsic disorderness and folding uponbinding of proteins

Abstract

The sequence-structure-function paradigm in biology states that proteins 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 disorder proteins (IDPs). Metamorphic proteins can fold into multiple native structures and perform multiple functions. IDPs, on the contrary, remain unstructured at physiological conditions, but can fold to unique structure upon binding to a target protein and show functionality. Here, we present a statistical mechanics model of protein folding with multiple native states and analyze their folding phase diagrams. While recovering classic sequence-structure-function paradigm for single native state, our model shows metamorphicity at lower number of native states. An expansion of unfolded region in the phase diagram at higher number of native states, making unfolded state as the stable state at physiological conditions, indicates the emergence of 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 folded region upon biasing, increasing the folding propensity of the system, with folding towards 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. Significance StatementProteins exhibit remarkable structural diversity, from having unique single native structure to having no particular structure but an inherently disordered ensemble that usually attains a single structure upon binding to another target. Here, we present a general statistical mechanics model of protein folding that reproduces single native state folding, metamorphicity, intrinsic disorder, and bindinginduced folding by incorporating multiple native states. A notable increase in propensity of being in unfolded state, resembling intrinsic disorder at physiological conditions, for system with larger number of native state was shown. Introduction of a bias was shown to increase the folding propensity of such proteins directed toward a specific native state. The models ability to capture a wide range of structural diversity in proteins makes it highly versatile.