Determining accurate conformational ensembles of intrinsically disordered proteins at atomic resolution

TL;DR

This paper introduces a method to accurately determine the atomic structure of disordered proteins by combining simulations with experimental data.

Contribution

A novel maximum entropy reweighting procedure is introduced to integrate MD simulations with NMR and SAXS data for accurate IDP ensembles.

Findings

IDP ensembles from different MD force fields converge when combined with sufficient experimental data.

The maximum entropy reweighting method enables accurate, force-field independent conformational ensembles of IDPs.

The approach integrates simulations with experimental datasets to improve atomic resolution modeling of disordered proteins.

Abstract

Determining accurate atomic resolution conformational ensembles of intrinsically disordered proteins (IDPs) is extremely challenging. Molecular dynamics (MD) simulations provide atomistic conformational ensembles of IDPs, but their accuracy is highly dependent on the quality of physical models, or force fields, used. In this work, we demonstrate how to determine accurate atomic resolution conformational ensembles of IDPs by integrating all-atom MD simulations with experimental data from nuclear magnetic resonance (NMR) spectroscopy and small-angle x-ray scattering (SAXS) with a simple, robust and fully automated maximum entropy reweighting procedure. We demonstrate that when this approach is applied with sufficient experimental data, IDP ensembles derived from different MD force fields converge to highly similar conformational distributions. The maximum entropy reweighting procedure presented here facilitates the integration of MD simulations with extensive experimental datasets and enables the calculation of accurate, force-field independent conformational ensembles of IDPs at atomic resolution.