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Review
. 2020 Feb:60:27-38.
doi: 10.1016/j.sbi.2019.10.009. Epub 2019 Dec 2.

Emerging consensus on the collapse of unfolded and intrinsically disordered proteins in water

Robert B Best  1
Affiliations
Review

Emerging consensus on the collapse of unfolded and intrinsically disordered proteins in water

Robert B Best. Curr Opin Struct Biol. 2020 Feb.

Abstract

Establishing the degree of collapse of unfolded or disordered proteins is a fundamental problem in biophysics, because of its relation to protein folding and to the function of intrinsically disordered proteins. However, until recently, different experiments gave qualitatively different results on collapse and there were large discrepancies between experiments and all-atom simulations. New methodology introduced in the past three years has helped to resolve the differences between experiments, and improvements in simulations have closed the gap between experiment and simulation. These advances have led to an emerging consensus on the collapse of disordered proteins in water.

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Conflict of interest statement

Declaration of Interest. The author declares no conflict of interest.

Figures

Figure 1:
Figure 1:
Background on unfolded protein collapse. (a) Polymer collapse illustrated from simulations of Val-100 with the ABSINTH model[67] (data from Zheng et al.[69]). Variation of radius of gyration Rg, end-end distance R and FRET efficiency E with temperature, all quantities being normalized by their respective values at the Θ temperature, Tθ. Here, increasing temperature is analogous to adding chemical denaturant, as both lessen the importance of intramolecular interactions. The transfer efficiency E was computed with a Förster radius of R0 ≈ Rθ. (b) Corresponding variation of length scaling exponent ν with temperature. Here ν was approximated from the scaling of internal distances for residues separated by a number of peptide bonds Np, i.e. 〈|ri−rj|2〉|i−j|=Np∝Npv. Shaded region respresents collapse not usually observed in unfolded or disordered proteins. Schematic figures illustrating degree of collapse are shown at top. (c) Discrepancy between FRET and SAXS experiments prior to recent methodological advances [33]: Rg for protein L and CspTm from FRET, and for protein L from SAXS as a function of denaturant concentration. Right axis shows equilibrium unfolded population of Protein L (magenta curve). (d) Comparison of Rg of unfolded proteins from simulations with the Rg of their respective folded states. [49] Length scaling laws with power law exponents of 1/3, 1/2 and 3/5 are shown.
Figure 2:
Figure 2:
Qualitative consistency of SAXS and FRET. (a) Guinier plots for R17 at different concentrations of GdmCl and urea. Note that the primary data and fits are offset on the y-axis for clariy; broken lines show the fitted curves without offset to compare slopes. (b) Guinier fits carried out for R17 in 4.96 M GdmCl with different fitting ranges [0, qmax], where qmaxRg is the number shown in the legend in (c). (c) Rg inferred from Guinier fits in (b), for different qmaxRg. (d) Primary FRET data for unfolded R17 in GdmCl and urea. (e) End-end distance R inferred from R17 FRET in GdmCl, assuming Gaussian chain or SAW polymer models as labelled. (f) Rg inferred from R using fixed conversion factor for Gaussian chain or SAW.
Figure 3:
Figure 3:
Ensemble refinement to interpret SAXS and FRET data. (a) SAXS and FRET data are recorded for the same unfolded protein (here: R17) under identical conditions as a function of denaturation concentration. (b) Unbiased simulations are performed using an implicit solvent model to generate an initial realistic molecular ensemble. (c) Bayesian ensemble refinement seeks to make the minimal perturbation to the simulation ensemble (by reweighting) in order to match the experimental data – ensemble averages after reweighting are overlaid on experimental data in (a) as thin curves. (d) Distance and radius of gyration distributions computed from the reweighted ensemble show an expansion with denaturant concentration. (e) Ensemble average R and Rg from ensemble refinement versus GdmCl concentration (red symbols) are compared with estimates from Gaussian chain (cyan) and SAW (navy) models from FRET and from Guinier analysis using the smallest practical range of q (green symbols).
Figure 4:
Figure 4:
Consistent analysis of multiple SAXS, FRET data sets. (a) Dependence of scaling exponent ν on denaturant concentration from SAXS data from Riback et al. [53] (red, blue symbols), and FRET data from Hofmann et al. [8] (grey symbols) and Borgia et al. [51] (green symbols). Analysis methods – Bayesian refinement or MFF – are given in legend in each case. (b) Dependence of scaling exponent on mean Kyte-Doolittle hydrophobicity for proteins studied by Borgia et al. [51], Fuertes et al. [52], Hofmann et al. [8] and Riback et al. [53]. Experimental methods and analysis methods are indicated in the legend.
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References

    1. Rubinstein M, Colby RH. Polymer Physics. Oxford University Press, Oxford, 2003.
    1. Alonso DOV, Dill KA. Solvent denaturation and stabilization of globular proteins. Biochemistry 1991, 30: 5974–5985. - PubMed
    1. Zerze Gül H and Best Robert B and Mittal Jeetain. Sequence and temperature-dependent properties of unfolded and disordered proteins from atomistic simulations. J Phys Chem B 2015,119: 14622–14630. - PMC - PubMed
    1. Holehouse AS, Pappu RV. Collapse transitions of proteins and the interplay among backbone, sidechain and solvent interactions. Ann Rev Biophys 2018, 47: 19–39. - PMC - PubMed

    2. ** Recent review of collapse in unfolded and disordered proteins, broken down into contributions from the backbone and different types of side-chain.

    1. Uversky VN, Gillespie JR, Fink AL. Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 2000, 41: 415–427. - PubMed

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