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    Successes and challenges in simulating the folding of large proteins

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    Author
    Gershenson, A.
    Gosavi, S.
    Wintrode, P.L.
    Date
    2020
    Journal
    The Journal of biological chemistry
    Publisher
    American Society for Biochemistry and Molecular Biology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1074/jbc.REV119.006794
    Abstract
    Computational simulations of protein folding can be used to interpret experimental folding results, to design new folding experiments, and to test the effects of mutations and small molecules on folding. However, whereas major experimental and computational progress has been made in understanding how small proteins fold, research on larger, multidomain proteins, which comprise the majority of proteins, is less advanced. Specifically, large proteins often fold via long-lived partially folded intermediates, whose structures, potentially toxic oligomerization, and interactions with cellular chaperones remain poorly understood. Molecular dynamics based folding simulations that rely on knowledge of the native structure can provide critical, detailed information on folding free energy landscapes, intermediates, and pathways. Further, increases in computational power and methodological advances have made folding simulations of large proteins practical and valuable. Here, using serpins that inhibit proteases as an example, we review native-centric methods for simulating the folding of large proteins. These synergistic approaches range from Gō and related structure-based models that can predict the effects of the native structure on folding to all-atom-based methods that include side-chain chemistry and can predict how disease-associated mutations may impact folding. The application of these computational approaches to serpins and other large proteins highlights the successes and limitations of current computational methods and underscores how computational results can be used to inform experiments. These powerful simulation approaches in combination with experiments can provide unique insights into how large proteins fold and misfold, expanding our ability to predict and manipulate protein folding. Copyright 2020 Gershenson et al.
    Keyword
    all-atom-based methods
    computer modeling
    MD simulations
    molecular dynamics
    multidomain proteins
    native-centric simulations
    protein folding
    protein misfolding
    serpin
    structure-based model (SBM)
    tertiary structure
    Show allShow less
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077477615&doi=10.1074%2fjbc.REV119.006794&partnerID=40&md5=e43c763c9c9ba56f8eb724d68ded858b; http://hdl.handle.net/10713/11625
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.REV119.006794
    Scopus Count
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