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Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins - PubMed

  • ️Tue Jan 01 2019

Review

Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

Supriyo Bhattacharya et al. Biomolecules. 2019.

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.

Keywords: conformational ensemble; drug design; intrinsically disordered protein; nuclear magnetic resonance; replica exchange molecular dynamics.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1

(A) Schematic free energy landscape of a folded protein; the folded state is comprised of an ensemble of structurally related states; (B) hypothetical intrinsically disordered protein (IDP) landscape showing four disordered (unfolded) states populated in free solution, separated by shallow energy barriers for rapid exchange; the multiple shallow minima in the disordered state free energy landscape indicate high structural flexibility; post translational modifications such as phosphorylation can stabilize one of the states over the others; a folded state is also present in the energy landscape, but only stabilized upon binding to a partner protein.

Figure 2
Figure 2

(A) Comparison between experimental (blue) and simulated 1DNH residual dipolar coupling (RDCs, red) from ensemble of α-synuclein generated by flexible-meccano and ASTEROIDS (a selection tool for ensemble representations of intrinsically disordered states); reproduced with permission from [95]; (B) comparison of experimental J coupling data from a disordered peptide with those calculated from ensembles obtained from replica exchange molecular dynamics (REMD) simulations with various force fields; The experimental 3JHN-Hα couplings are shown in gray shading (C) ensembles obtained from various force fields in cartoon representation; reproduced with permission from [69].

Figure 3
Figure 3

(A) Formation of a fast binding fuzzy complex between nucleoporin (red cartoon) and importinβ (grey surface), simulated using an all-atom molecular dynamics (MD) simulation; the binding sites on importin β and nucleoporin are colored in orange and cyan respectively; reproduced with permission from [101] (

https://doi.org/10.1016/j.cell.2015.09.047

) under the terms of the Creative Commons Attribution License (CC BY);

http://creativecommons.org/licenses/by/4.0/

(B) schematic demonstration of conformational selection and induced fit binding mechanisms; in the absence of binding partner, the IDP switches between the non-binding (blue) and binding (red) conformations; in conformational selection, the IDP binds to the partner protein in the binding conformation without any structural rearrangement; for induced fit binding, the IDP initially encounters the partner using the non-binding conformation, then adopts the binding conformation in presence of the partner; reproduced with permission from ref. [108] (C) coarse-grain free energy landscape showing a combined conformational selection and induced fit binding of a disordered C terminal segment of the measles virus nucleoprotein to the X domain of the measles virus phosphoprotein; reproduced with permission from ref. [103]; Copyright 2013 national Academy of Sciences.

Figure 4
Figure 4

Example computational protocol for identifying drug candidates for IDPs; the IDP structural ensemble is clustered into representative conformations and druggable pockets are identified in each conformation; these pockets are further filtered by criteria such as hydrophobicity, backbone flexibility, and allosteric communication with functional sites. Virtual screening is performed in each pocket and final hits are selected based on high affinity in multiple IDP conformations.

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