Towards accurate, force field independent conformational ensembles of intrinsically disordered proteins

Determining accurate atomic resolution conformational ensembles of intrinsically disordered proteins (IDPs) is extremely challenging. Molecular dynamics (MD) computer simulations provide atomically detailed conformational ensembles of IDPs, but their accuracy is highly dependent on the quality of the underlying physical models, or force fields , used. Integrative methods that combine experimental data with computational models offer a promising approach to address force field limitations and generate accurate conformational ensembles of IDPs, shedding light on their functional mechanisms. Here, we present a simple and robust maximum entropy reweighting procedure to refine atomic resolution conformational ensembles of IDPs with large experimental datasets consisting of several different types of data. We apply this approach to refine structural ensembles obtained from long timescale MD simulations and generate IDP ensembles with substantially improved agreement with a variety of nuclear magnetic resonance (NMR) and small-angle X-ray scattering (SAXS) measurements. We ask if reweighted IDP ensembles derived from MD simulations run with different force fields converge to similar conformational distributions when extensive experimental datasets are used for refinement. We find that in favorable cases IDP ensembles derived from different force fields become highly similar after reweighting with experimental data. The maximum entropy reweighting procedure presented here enables the integration of atomic resolution MD simulations with extensive experimental datasets and can facilitate the elucidation of accurate, force field independent conformational ensembles of IDPs.