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

Pietrek, L. M., Stelzl, L. S., & Hummer, G. (2020). Hierarchical Ensembles of Intrinsically Disordered Proteins at Atomic Resolution in Molecular Dynamics Simulations. Journal of Chemical Theory and Computation, 16(1), 725-737. doi:10.1021/acs.jctc.9b00809.

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 Creators:
Pietrek, Lisa M.1, Author              
Stelzl, Lukas S.1, Author              
Hummer, Gerhard1, 2, Author              
Affiliations:
1Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
2Institute for Biophysics, Goethe University Frankfurt, Frankfurt, Germany, ou_persistent22              

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 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 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.

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Language(s): eng - English
 Dates: 2019-08-102019-12-062020-01-14
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acs.jctc.9b00809
BibTex Citekey: pietrek_hierarchical_2019
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Title: Journal of Chemical Theory and Computation
  Other : J. Chem. Theory Comput.
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 16 (1) Sequence Number: - Start / End Page: 725 - 737 Identifier: ISSN: 1549-9618
CoNE: https://pure.mpg.de/cone/journals/resource/111088195283832