Determining accurate conformational ensembles of intrinsically disordered proteins at atomic resolution

Kaushik Borthakur, Thomas R. Sisk, Francesco P. Panei, Massimiliano Bonomi and Paul Robustelli ()
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Kaushik Borthakur: Dartmouth College
Thomas R. Sisk: Dartmouth College
Francesco P. Panei: Université Paris Cité, CNRS UMR 3528, Computational Structural Biology Unit
Massimiliano Bonomi: Université Paris Cité, CNRS UMR 3528, Computational Structural Biology Unit
Paul Robustelli: Dartmouth College

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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. Here, 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 in favorable cases, where IDP ensembles obtained from different MD force fields are in reasonable initial agreement with experimental data, reweighted ensembles obtained with this approach converge to highly similar conformational distributions. The maximum entropy reweighting procedure presented here facilitates the integration of MD simulations with extensive experimental datasets and demonstrates progress towards the calculation of accurate, force-field independent conformational ensembles of IDPs at atomic resolution.

Date: 2025
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DOI: 10.1038/s41467-025-64098-3

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