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

Utsab R Shrestha,Loukas Petridis,Jeremy C Smith

doi:10.1038/s42003-021-01759-1

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.

Highlights

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs)
We report that Hamiltonian replica-exchange MD (HREMD) produces configurational ensembles consistent with SAXS, SANS, and nuclear magnetic resonance (NMR) experiments for three IDPs with markedly different sequence characteristics: Histatin 5 (24 residues) and Sic 1 (92 residues), both of which have an abundance of positively charged residues, and the N
The histograms of a radius of gyration (Rg) show the IDPs adopt a continuum of collapsed to extended structures (Fig. 1a–c)

Summary

Introduction

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). A common and successful approach to determine an IDP configurational ensemble is to force the MD results to match existing experiments, either by biasing the MD potential[35,36] or by a posteriori reweighting the ensemble of the MD population[37,38] One challenge for these methods is degeneracy, that is, distinct 3D conformations may yield the same observable, which may lead to overfitting. Bayesian maximum entropy optimization approaches, which aim to perturb the MD ensemble as little as possible, have been employed to avoid overfitting[35,38,39] These approaches always require a prior experimental measurement and do not afford a predictive understanding of IDPs. Recently, by enhancing the configurational sampling of MD simulations using Hamiltonian replica-exchange MD (HREMD) the configurational ensemble of an IDP was generated that is in quantitative agreement to SAXS, SANS, and NMR measurements without biasing or reweighting the simulations[40,41]. We report that HREMD produces configurational ensembles consistent with SAXS, SANS, and NMR experiments for three IDPs with markedly different sequence characteristics: Histatin 5 (24 residues) and Sic 1 (92 residues), both of which have an abundance of positively charged residues, and the N-

Methods

Results

Conclusion