Abstract
Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field.
Highlights
Disordered proteins (IDPs) have emerged as an important class of biomolecules that are involved in a variety of cellular functions, ranging from signaling to gene expression, chaperoning, and cellular transport [1]
Due to their dynamic nature, many intrinsically disordered protein (IDP) can interact with multiple proteins with low affinity but high specificity, enabling them to act as hubs in signaling networks, or adapters for multi-protein scaffolds [1]
Ensemble by random sampling of polypeptide conformations, MD based methods perform the conformational sampling using molecular dynamics algorithms, which simulate the dynamic behavior of IDPs under physiological conditions in a solvent environment
Summary
Disordered proteins (IDPs) have emerged as an important class of biomolecules that are involved in a variety of cellular functions, ranging from signaling to gene expression, chaperoning, and cellular transport [1]. These proteins lack a definite folded structure and adopt an ensemble of conformations in their physiological environment. The IDPs are studied using a combination of techniques, including nuclear magnetic resonance (NMR), small angle X-ray scattering (SAXS), circular dichroism (CD), and single molecule spectroscopy [3] These methods provide information about local residue contacts and side chain orientations, secondary structure content, as well as the dynamics and lifetime of such contacts. We summarize the challenges involved in applying these methods and possible future directions in this field
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
