A new approach to 3D modeling of inhomogeneous populations of viral regulatory RNA

Research output: Contribution to journalArticlepeer-review

Abstract

Tertiary structure (3D) is the physical context of RNA regulatory activity. Retroviruses are RNA viruses that replicate through the proviral DNA intermediate transcribed by hosts. Proviral transcripts form inhomogeneous populations due to variable structural ensembles of overlapping regulatory RNA motifs in the 5′-untranslated region (UTR), which drive RNAs to be spliced or translated, and/or dimerized and packaged into virions. Genetic studies and structural techniques have provided fundamental input constraints to begin predicting HIV 3D conformations in silico. Using SimRNA and sets of experimentally-determined input constraints of HIVNL4-3 trans-activation responsive sequence (TAR) and pairings of unique-5′ (U5) with dimerization (DIS) or AUG motifs, we calculated a series of 3D models that differ in proximity of 5′-Cap and the junction of TAR and PolyA helices; configuration of primer binding site (PBS)-segment; and two host cofactors binding sites. Input constraints on U5-AUG pairings were most compatible with intramolecular folding of 5′-UTR motifs in energetic minima. Introducing theoretical constraints predicted metastable PolyA region drives orientation of 5′-Cap with TAR, U5 and PBS-segment helices. SimRNA and the workflow developed herein provides viable options to predict 3D conformations of inhomogeneous populations of large RNAs that have been intractable to conventional ensemble methods.

Original languageEnglish (US)
Article number1108
JournalViruses
Volume12
Issue number10
DOIs
StatePublished - Oct 2020

Bibliographical note

Funding Information:
The College of Veterinary Medicine, University of Minnesota-Twin Cities to K.B.-L. and The Ohio State University to P.S.O.

Keywords

  • 5′-cap
  • Centroid
  • Complex 5′-untranslated region
  • Intramolecular folding
  • Medoid
  • RNA structure ensemble
  • Retrovirus
  • Supercomputer cluster

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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