Describing sequence–ensemble relationships for intrinsically disordered proteins

Abstract

Synopsis Intrinsically disordered proteins participate in important protein-protein and protein-nucleic acid interactions and control cellular phenotypes through their prominence as dynamic organizers of transcriptional, post-transcriptional, and signaling networks. These proteins challenge the tenets of the structure-function paradigm and their functional mechanisms remain a mystery given that they fail to fold autonomously into specific structures. Solving this mystery requires a first principles understanding of the quantitative relationships between information encoded in the sequences of disordered proteins and the ensemble of conformations they sample. Advances in quantifying sequence-ensemble relationships have been facilitated through a four-way synergy between bioinformatics, biophysical experiments, computer simulations, and polymer physics theories. Here, we review these advances and the resultant insights that allow us to develop a concise quantitative framework for describing sequence-ensemble relationships of intrinsically disordered proteins.

Single-molecule spectroscopy reveals polymer effects of disordered proteins in crowded environments

“…PEG is widely used for biomedical applications (31) and for mimicking inert crowding agents (13,26). Previous work has shown that the conformational properties of IDPs strongly depend on their amino acid sequence composition and charge patterning (8,11,27,28,(32)(33)(34). Here we investigate the effect of crowding on four different IDP sequences that span a broad range of net charge per residue and average hydrophobicity ( Fig.…”

“…These "intrinsically disordered proteins" (IDPs) are involved in many crucial cellular processes, such as transcription, translation, and signal transduction; their functional and conformational properties are thus of great interest for a wide range of biological questions. Important advances in understanding the structures of IDPs have been made over the past decade, especially with spectroscopic techniques, e.g., NMR (3,4), single-molecule fluorescence (5)(6)(7), and with atomistic and coarse-grained molecular simulations (8)(9)(10). In contrast with the stable folded structures we are familiar with from 50 y of structural biology, IDPs comprise highly heterogeneous and dynamic ensembles of conformations, which either lack stable tertiary structure altogether or fold only on binding their cellular targets (4).…”

Temperature-dependent solvation modulates the dimensions of disordered proteins

“…Given the presence of varying degrees of disorder in unbound and bound states (5), a general framework for the description of the physicochemical properties of IDPs will aid our understanding of the molecular mechanisms underlying their function. Such a framework is beginning to emerge from recent work in which concepts from polymer physics have been found to capture very successfully key aspects of the global conformational and dynamic properties of IDPs and unfolded proteins in general (6). These include the role of charge interactions (7,8), protein-solvent interactions (9)(10)(11)(12)(13), scaling laws (14-16), reconfiguration dynamics (17), and the effect of internal friction (18)(19)(20)(21).…”

Intrinsically Disordered Proteins as Drug Targets

“…16,18,46 Small Angle X-ray Scattering 47,48 or single-molecule fluorescence 28,49-51 as well as employing atomistic and coarse-grained simulations. 20,[52][53][54][55] By using the above-mentioned techniques some approximations have been reported to design drugs targeting IDPs. The common approaches are (I) directly bind to the disordered ensemble neutralizing the protein function/dysfunction and (II) bind to a binding partner and inhibit IDP binding or stabilize its bound state.…”