IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1008323.html
   My bibliography  Save this article

Validation of DBFOLD: An efficient algorithm for computing folding pathways of complex proteins

Author

Listed:
  • Amir Bitran
  • William M Jacobs
  • Eugene Shakhnovich

Abstract

Atomistic simulations can provide valuable, experimentally-verifiable insights into protein folding mechanisms, but existing ab initio simulation methods are restricted to only the smallest proteins due to severe computational speed limits. The folding of larger proteins has been studied using native-centric potential functions, but such models omit the potentially crucial role of non-native interactions. Here, we present an algorithm, entitled DBFOLD, which can predict folding pathways for a wide range of proteins while accounting for the effects of non-native contacts. In addition, DBFOLD can predict the relative rates of different transitions within a protein’s folding pathway. To accomplish this, rather than directly simulating folding, our method combines equilibrium Monte-Carlo simulations, which deploy enhanced sampling, with unfolding simulations at high temperatures. We show that under certain conditions, trajectories from these two types of simulations can be jointly analyzed to compute unknown folding rates from detailed balance. This requires inferring free energies from the equilibrium simulations, and extrapolating transition rates from the unfolding simulations to lower, physiologically-reasonable temperatures at which the native state is marginally stable. As a proof of principle, we show that our method can accurately predict folding pathways and Monte-Carlo rates for the well-characterized Streptococcal protein G. We then show that our method significantly reduces the amount of computation time required to compute the folding pathways of large, misfolding-prone proteins that lie beyond the reach of existing direct simulation. Our algorithm, which is available online, can generate detailed atomistic models of protein folding mechanisms while shedding light on the role of non-native intermediates which may crucially affect organismal fitness and are frequently implicated in disease.Author summary: Many proteins must adopt a specific structure in order to function. Computational simulations have been used to shed light on the mechanisms of protein folding, but unfortunately, realistic simulations can typically only be run for small proteins, due to severe limits in computational speed. Here, we present a method to solve this problem, whereby instead of directly simulating folding from an unfolded state, we run simulations that allow for computation of equilibrium folding free energies, alongside high temperature simulations to compute unfolding rates. From these quantities, folding rates can be computed using detailed balance. Importantly, our method can account for the effects of nonnative contacts which transiently form during folding and must be broken prior to adoption of the native state. Such contacts, which are often excluded from simple models of folding, may crucially affect real protein folding pathways and are often observed in folding intermediates implicated in disease.

Suggested Citation

  • Amir Bitran & William M Jacobs & Eugene Shakhnovich, 2020. "Validation of DBFOLD: An efficient algorithm for computing folding pathways of complex proteins," PLOS Computational Biology, Public Library of Science, vol. 16(11), pages 1-32, November.
  • Handle: RePEc:plo:pcbi00:1008323
    DOI: 10.1371/journal.pcbi.1008323
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008323
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1008323&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1008323?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jian Tian & Jaie C Woodard & Anna Whitney & Eugene I Shakhnovich, 2015. "Thermal Stabilization of Dihydrofolate Reductase Using Monte Carlo Unfolding Simulations and Its Functional Consequences," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-27, April.
    2. Ron Geller & Sebastian Pechmann & Ashley Acevedo & Raul Andino & Judith Frydman, 2018. "Hsp90 shapes protein and RNA evolution to balance trade-offs between protein stability and aggregation," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Pei Zhao & Chao Wang & Shuhong Sun & Xi Wang & William E. Balch, 2024. "Tracing genetic diversity captures the molecular basis of misfolding disease," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Adam Catching & Ming Yeh & Simone Bianco & Sara Capponi & Raul Andino, 2023. "A tradeoff between enterovirus A71 particle stability and cell entry," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pcbi00:1008323. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.