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Controlling Structural Bias in Intrinsically Disordered Proteins Using Solution Space Scanning

View ORCID ProfileAlex S Holehouse, View ORCID ProfileShahar Sukenik
doi: https://doi.org/10.1101/752378
Alex S Holehouse
Department of Biomedical Engineering and Center for Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, USADepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • For correspondence: alex.holehouse@wustl.edu
Shahar Sukenik
Department of Chemistry and Chemical Biology, UC Merced, Merced, CA 95340, USA
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Abstract

Intrinsically disordered proteins or regions (IDRs) differ from their well-folded counterparts by lacking a stable tertiary state. Instead, IDRs exist in an ensemble of conformations and often possess localized, loosely held residual structure that can be a key determinant of their activity. With no extensive network of non-covalent bonds and a high propensity for exposed surface areas, the various features of an IDR’s ensemble – including local residual structure and global conformational biases – are an emergent property of both the amino acid sequence and the solution environment. Here, we attempt to understand how shifting solution conditions can alter an IDR’s ensemble. We present an efficient computational method to alter solution-protein interactions we term Solution Space (SolSpace) Scanning. SolSpace scanning uses all-atom Monte-Carlo simulations to construct ensembles under a wide range of distinct solution conditions. By tuning the interactions of specific protein moieties with the solution in a systematic manner we can both enhance and reduce local residual structure. This approach allows the ‘design’ of distinct residual structures in IDRs, offering an alternative approach to mutational studies for exploring sequence-to-ensemble relationships. Our results raise the possibility of solution-based regulation of protein functions both outside and within the dynamic solution environment of cells.

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  • https://solutionspacescanner.readthedocs.io/en/latest/

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 30, 2019.
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Controlling Structural Bias in Intrinsically Disordered Proteins Using Solution Space Scanning
Alex S Holehouse, Shahar Sukenik
bioRxiv 752378; doi: https://doi.org/10.1101/752378
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Controlling Structural Bias in Intrinsically Disordered Proteins Using Solution Space Scanning
Alex S Holehouse, Shahar Sukenik
bioRxiv 752378; doi: https://doi.org/10.1101/752378

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