Hierarchical Ensembles of Intrinsically Disordered Proteins at Atomic Resolution in Molecular Dynamics Simulations

Abstract

Intrinsically disordered proteins (IDPs) constitute a large fraction of the human proteome and are critical in the regulation of cellular processes. A detailed understanding of the conformational dynamics of IDPs could help to elucidate their roles in health and disease. However the inherent flexibility of IDPs makes structural studies and their interpretation challenging. Molecular dynamics (MD) simulations could address this challenge in principle, but inaccuracies in the simulation models and the need for long simulations have stymied progress. To overcome these limitations, we adopt an hierarchical approach that builds on the "flexible meccano" model of Bernadó et al. (J. Am. Chem. Soc. 2005, 127, 17968-17969). First, we exhaustively sample small IDP fragments in all-atom simulations to capture local structure. Then, we assemble the fragments into full-length IDPs to explore the stereochemically possible global structures of IDPs. The resulting ensembles of three-dimensional structures of full-length IDPs are highly diverse, much more so than in standard MD simulation.For the paradigmatic IDP α-synuclein, our ensemble captures both local structure, as probed by nuclear magnetic resonance (NMR) spectroscopy, and its overall dimension, as obtained from small-angle X-ray scattering (SAXS) in solution. By generating representative and meaningful starting ensembles, we can begin to exploit the massive parallelism afforded by current and future high-performance computing resources for atomic-resolution characterization of IDPs.

Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

“…Next, we investigated the conformational properties of A182-S197 with MD simulations. For the simulations, we used the state-of-the-art force field/water model that accurately reproduced NMR parameters of the intrinsically disordered protein αsynuclein 26 . In agreement with the NMR analysis, residues next to R189 populate transient α-helical structure (Fig.…”

Liquid network connectivity regulates the stability and composition of biomolecular condensates with many components

“…Although atomistic descriptions are needed to investigate the microscopic determinants of LLPS-such as the impact of chemical modifications, specific intermolecular interactions, and conformational dynamics-due to the exponential scaling of the search space with protein size (49), sampling the formation of protein condensates atomistically is currently unfeasible. Atomistic simulations of relevant systems for understanding protein LLPS are scarce and have been limited to aggregates of ∼10 to 20 small proteins (e.g., a 56-residue peptide) that are formed prior to simulation (50).…”

Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation

“…Atomistic MD simulations HCG (Pietrek et al, 2020) enables us to generate statistically independent and chemically-meaningful conformations of a biomolecular condensate with atomic resolution, which serve as starting points for atomistic MD simulations. Atomic-resolution models of clusters of the C-terminal disordered domain of were generated for both Wt protein and the 12D mutant.…”