TY - JOUR
T1 - Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression
AU - Yan, Shuting
AU - Zhu, Qiyao
AU - Jain, Swati
AU - Schlick, Tamar
N1 - Funding Information:
We gratefully acknowledge funding from the National Science Foundation RAPID Award 2030377 from the Division of Mathematical Science and the Division of Chemistry, National Science Foundation Award DMS-2151777 from the Division of Mathematical Sciences, National Institutes of Health R35GM122562 Award from the National Institute of General Medical Sciences, and Philip-Morris International to T. Schlick.
Funding Information:
We thank Shereef Elmetwaly for technical assistance and David Ackerman, Stratos Efstathiadis, and Shenglong Wang from the NYU High-Performance Computing facilities for providing our group dedicated resources to perform this work. We gratefully acknowledge funding from the National Science Foundation RAPID Award 2030377 from the Division of Mathematical Science and the Division of Chemistry, National Science Foundation Award DMS-2151777 from the Division of Mathematical Sciences, National Institutes of Health R35GM122562 Award from the National Institute of General Medical Sciences, and Philip-Morris International to T. Schlick.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The SARS-CoV-2 frameshifting element (FSE), a highly conserved mRNA region required for correct translation of viral polyproteins, defines an excellent therapeutic target against Covid-19. As discovered by our prior graph-theory analysis with SHAPE experiments, the FSE adopts a heterogeneous, length-dependent conformational landscape consisting of an assumed 3-stem H-type pseudoknot (graph motif 3_6), and two alternative motifs (3_3 and 3_5). Here, for the first time, we build and simulate, by microsecond molecular dynamics, 30 models for all three motifs plus motif-stabilizing mutants at different lengths. Our 3_6 pseudoknot systems, which agree with experimental structures, reveal interconvertible L and linear conformations likely related to ribosomal pausing and frameshifting. The 3_6 mutant inhibits this transformation and could hamper frameshifting. Our 3_3 systems exhibit length-dependent stem interactions that point to a potential transition pathway connecting the three motifs during ribosomal elongation. Together, our observations provide new insights into frameshifting mechanisms and anti-viral strategies.
AB - The SARS-CoV-2 frameshifting element (FSE), a highly conserved mRNA region required for correct translation of viral polyproteins, defines an excellent therapeutic target against Covid-19. As discovered by our prior graph-theory analysis with SHAPE experiments, the FSE adopts a heterogeneous, length-dependent conformational landscape consisting of an assumed 3-stem H-type pseudoknot (graph motif 3_6), and two alternative motifs (3_3 and 3_5). Here, for the first time, we build and simulate, by microsecond molecular dynamics, 30 models for all three motifs plus motif-stabilizing mutants at different lengths. Our 3_6 pseudoknot systems, which agree with experimental structures, reveal interconvertible L and linear conformations likely related to ribosomal pausing and frameshifting. The 3_6 mutant inhibits this transformation and could hamper frameshifting. Our 3_3 systems exhibit length-dependent stem interactions that point to a potential transition pathway connecting the three motifs during ribosomal elongation. Together, our observations provide new insights into frameshifting mechanisms and anti-viral strategies.
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U2 - 10.1038/s41467-022-31353-w
DO - 10.1038/s41467-022-31353-w
M3 - Article
C2 - 35879278
AN - SCOPUS:85134743720
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4284
ER -