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

• Published in: Journal of chemical theory and computation Vol. 16; no. 1; pp. 725 - 737
• Main Authors: Pietrek, Lisa M, Stelzl, Lukas S, Hummer, Gerhard
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.01.2020
• Subjects: Algorithms; alpha-Synuclein - chemistry; Amino Acid Sequence; Computer simulation; Dynamic structural analysis; Fragments; Humans; Intrinsically Disordered Proteins - chemistry; Molecular dynamics; Molecular Dynamics Simulation; NMR; Nuclear magnetic resonance; Protein Conformation; Proteins; Resonance scattering; Scattering, Small Angle; Simulation; Small angle X ray scattering; Stereoisomerism; X-Ray Diffraction
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.9b00809

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 a hierarchical approach that builds on the “flexible-meccano” model reported by Bernadó et al. (J. Am. Chem. Soc. 2005, 127, 17968–17969). First, we exhaustively sample small IDP fragments in all-atom simulations to capture their local structures. 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 the local structure, as probed by nuclear magnetic resonance spectroscopy, and its overall dimension, as obtained from small-angle X-ray scattering 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.