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<p>Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the three-dimensional (3D) structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen–deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~10<sup>5</sup>–10<sup>7</sup> longer than that of canonical base pairs. Mutations that shorten the apparent lifetime of the ground state without affecting its 3D structure decreased exoribonuclease resistance in vitro and impaired virus replication in cells. Additionally, we observed this exceptionally long-lived ground state in xrRNAs from diverse infectious mosquito-borne flaviviruses. These results demonstrate the biological importance of the lifetime of a preorganized ground state and further suggest that elucidating the lifetimes of dominant 3D structures of biomolecules may be crucial for understanding their behaviors and functions.</p><p></p>

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Lifetime of ground conformational state determines the activity of structured RNA

  • 期刊论文

  • 发表日期：

    2025年2月12日

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  • Rhese D. Thompson,
  • Derek L. Carbaugh,
  • Joshua R. Nielsen,
  • Ciara M. Witt,
  • Edgar M. Faison,
  • Rita M. Meganck,
  • Atul Rangadurai,
  • Bo Zhao,
  • Jeffrey P. Bonin,
  • Nathan I. Nicely,
  • William F. Marzluff,
  • Aaron T. Frank,
  • Helen M. Lazear,
  • Qi Zhang

摘要

Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the three-dimensional (3D) structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen–deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~105–107 longer than that of canonical base pairs. Mutations that shorten the apparent lifetime of the ground state without affecting its 3D structure decreased exoribonuclease resistance in vitro and impaired virus replication in cells. Additionally, we observed this exceptionally long-lived ground state in xrRNAs from diverse infectious mosquito-borne flaviviruses. These results demonstrate the biological importance of the lifetime of a preorganized ground state and further suggest that elucidating the lifetimes of dominant 3D structures of biomolecules may be crucial for understanding their behaviors and functions.