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. 2021 Feb 23;4(1):243.
doi: 10.1038/s42003-021-01759-1.

Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Utsab R Shrestha  1 , Jeremy C Smith  1   2 , Loukas Petridis  3   4
Affiliations

Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Utsab R Shrestha et al. Commun Biol. .

Abstract

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD (HREMD) led to unbiased and accurate ensembles, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of varying sequence properties using two recently optimized force fields, indicating the general applicability of HREMD for IDPs. We further demonstrate that, unlike HREMD, standard MD can reproduce experimental NMR chemical shifts, but not small-angle scattering data, suggesting chemical shifts are insufficient for testing the validity of IDP ensembles. Surprisingly, we reveal that despite differences in their sequence, the inter-chain statistics of all three IDPs are similar for short contour lengths (< 10 residues). The results suggest that the major hurdle of generating an accurate unbiased ensemble for IDPs has now been largely overcome.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Comparison of experiemntal and calculated global structural properties of IDPs.
a–c The histograms of Rg of a Histatin 5, b Sic 1, and c SH4UD obtained from MD simulations. The inverted triangles indicate the average Rg of each simulation. d–f The SAXS profiles calculated from simulations (using SWAXS) are compared to experiments for d Histatin 5, e Sic 1, and f SH4UD. Insets: SAXS data are zoomed at low-q values to show the differences in intensity for different force fields and sampling methods. In all cases, the color code indicates the force fields, a03ws or a99SB-disp, and sampling methods, standard MD or HREMD (Supplementary Tables 1 and 2). HREMD results are from the lowest rank replica of the simulations shown by the bold-italics font in Supplementary Table 2. SANS data of SH4UD are shown in Supplementary Fig. 2.
Fig. 2
Fig. 2. Comparison of experimental and calculated local structural properties of IDPs.
Comparison between the ensemble-averaged experimental (bars) and calculated (symbols) NMR secondary chemical shifts (ΔCS) of backbone atoms a NH, b Cα, and c Cβ for SH4UD. ΔCS RMSE of backbone atoms with respect to experimental values (bars), as defined in Eq. (6), for d Histatin 5, e Sic 1, and f SH4UD. The error bars in ΔCS RMSE (d–f) are the standard error of the mean as defined in Eq. (4). The color code indicates the force field and sampling method used. The theoretical NMR chemical shifts are calculated using SHIFTX2. The prediction values of SHIFTX2 have RMS errors of 1.12, 0.44, 0.52, 0.17, and 0.12 p.p.m. for backbone atoms NH, Cα, Cβ, HN, and Hα, respectively.
Fig. 3
Fig. 3. Chain statistics of IDPs.
a The orientational correlation function as a function of the pairwise residue sequence separation, s. For s<5, Cs is fitted by Cs=e−s/k for each IDP, where k is the number of Cα atom pair related to persistence length (lp) by lp = k × 0.38 nm. For s≥5 the power law Cs~s−3/2 applies only for Sic 1, whereas for Histatin 5 and SH4UD the correlation vanishes. b–d The average pairwise geometric distance (Rs) between Cα atoms of two residues at separation s for b Histatin 5, c Sic 1, and d SH4UD. The data are fitted by Eq. (2) in two regimes, s ≤ 10 (blue) and s > 10 (red). The error bars are smaller than the symbol size.
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