Intrinsically disordered proteins: Ensembles at the limits of Anfinsen's dogma

Abstract

Intrinsically disordered proteins (IDPs) are proteins that lack rigid 3D structure. Hence, they are often misconceived to present a challenge to Anfinsen's dogma. However, IDPs exist as ensembles that sample a quasi-continuum of rapidly interconverting conformations and, as such, may represent proteins at the extreme limit of the Anfinsen postulate. IDPs play important biological roles and are key components of the cellular protein interaction network (PIN). Many IDPs can interconvert between disordered and ordered states as they bind to appropriate partners. Conformational dynamics of IDPs contribute to conformational noise in the cell. Thus, the dysregulation of IDPs contributes to increased noise and “promiscuous” interactions. This leads to PIN rewiring to output an appropriate response underscoring the critical role of IDPs in cellular decision making. Nonetheless, IDPs are not easily tractable experimentally. Furthermore, in the absence of a reference conformation, discerning the energy landscape representation of the weakly funneled IDPs in terms of reaction coordinates is challenging. To understand conformational dynamics in real time and decipher how IDPs recognize multiple binding partners with high specificity, several sophisticated knowledge-based and physics-based in silico sampling techniques have been developed. Here, using specific examples, we highlight recent advances in energy landscape visualization and molecular dynamics simulations to discern conformational dynamics and discuss how the conformational preferences of IDPs modulate their function, especially in phenotypic switching. Finally, we discuss recent progress in identifying small molecules targeting IDPs underscoring the potential therapeutic value of IDPs. Understanding structure and function of IDPs can not only provide new insight on cellular decision making but may also help to refine and extend Anfinsen's structure/function paradigm.

Addressing Drug Resistance in Cancer: A Team Medicine Approach

“…Intrinsically disordered proteins (IDPs) are proteins that lack a rigid 3D structure and exist as ensembles of interconverting conformations [ 40 ]. Because they are highly malleable, IDPs interact with multiple partners and thus occupy hub positions in PINs.…”

Structure and Transition Dynamics of Intrinsically Disordered Proteins Probed by Single-Molecule Spectroscopy

“…4 Contrary to the folded proteins which acquire thermally accessible states (known to depict the ensembleaverage property), IDPs possess a collection (an ensemble) of distinct conformations. 5 Hence, disordered proteins sample the free-energy surfaces comprising several local energy minima distinguished by low-energy barriers as compared to the ordered proteins having a distinct global energy minimum. 5 Despite resembling the structural malleability in their native state, many IDPs show partial folding patterns upon interaction with different binding counterparts, viz., other biomolecules and small molecules.…”

“…5 Hence, disordered proteins sample the free-energy surfaces comprising several local energy minima distinguished by low-energy barriers as compared to the ordered proteins having a distinct global energy minimum. 5 Despite resembling the structural malleability in their native state, many IDPs show partial folding patterns upon interaction with different binding counterparts, viz., other biomolecules and small molecules. In the bound forms, IDPs can remain in a tightly folded conformer or adopt different conformations depending on the nature of their binding counterparts.…”

“…7 According to the interaction or binding pattern, IDPs are generally classified into foldable, unfoldable, and nonfoldable proteins. 5 Generally, foldable IDPs show partial folding in the presence of an artificial crowded environment as well as inside the living cells. Unfoldable IDPs experience further unfolding, while the nonfoldable IDPs remain in the unstructured conformer, even upon exposure to the crowding agents.…”

“…Several computational and sequence-based studies revealed that the number of disordered residues is pronounced as a function of the complexity of the organism, starting from ∼30 (for bacteria and archaea) to a much higher number for eukaryotic organisms . Contrary to the folded proteins which acquire thermally accessible states (known to depict the ensemble-average property), IDPs possess a collection (an ensemble) of distinct conformations . Hence, disordered proteins sample the free-energy surfaces comprising several local energy minima distinguished by low-energy barriers as compared to the ordered proteins having a distinct global energy minimum …”