TY - JOUR
T1 - A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States
AU - Zerze, Gül H.
AU - Piaggi, Pablo M.
AU - Debenedetti, Pablo G.
N1 - Funding Information:
P.G.D. acknowledges the support of the National Science Foundation (Grant CHE-1856704). P.M.P. was supported by an Early Postdoc.Mobility fellowship from the Swiss National Science Foundation and by the center Chemistry in Solution and at Interfaces funded by the DOE under Award DE-SC0019394. The simulations presented in this work are performed on computational resources managed and supported by Princeton Research Computing, a consortium of groups including the Princeton Institute for Computational Science and Engineering (PICSciE) and the Office of Information Technology’s High Performance Computing Center and Visualization Laboratory at Princeton University.
Publisher Copyright:
© 2021 American Chemical Society
PY - 2021/12/23
Y1 - 2021/12/23
N2 - An important characteristic of RNA folding is the adoption of alternative configurations of similar stability, often referred to as misfolded configurations. These configurations are considered to compete with correctly folded configurations, although their rigorous thermodynamic and structural characterization remains elusive. Tetraloop motifs found in large ribozymes are ideal systems for an atomistically detailed computational quantification of folding free energy landscapes and the structural characterization of their constituent free energy basins, including nonnative states. In this work, we studied a group of closely related 10-mer tetraloops using a combined parallel tempering and metadynamics technique that allows a reliable sampling of the free energy landscapes, requiring only knowledge that the stem folds into a canonical A-RNA configuration. We isolated and analyzed unfolded, folded, and misfolded populations that correspond to different free energy basins. We identified a distinct misfolded state that has a stability very close to that of the correctly folded state. This misfolded state contains a predominant population that shares the same structural features across all tetraloops studied here and lacks the noncanonical A-G base pair in its loop portion. Further analysis performed with biased trajectories showed that although this competitive misfolded state is not an essential intermediate, it is visited in most of the transitions from unfolded to correctly folded states. Moreover, the tetraloops can transition from this misfolded state to the correctly folded state without requiring extensive unfolding.
AB - An important characteristic of RNA folding is the adoption of alternative configurations of similar stability, often referred to as misfolded configurations. These configurations are considered to compete with correctly folded configurations, although their rigorous thermodynamic and structural characterization remains elusive. Tetraloop motifs found in large ribozymes are ideal systems for an atomistically detailed computational quantification of folding free energy landscapes and the structural characterization of their constituent free energy basins, including nonnative states. In this work, we studied a group of closely related 10-mer tetraloops using a combined parallel tempering and metadynamics technique that allows a reliable sampling of the free energy landscapes, requiring only knowledge that the stem folds into a canonical A-RNA configuration. We isolated and analyzed unfolded, folded, and misfolded populations that correspond to different free energy basins. We identified a distinct misfolded state that has a stability very close to that of the correctly folded state. This misfolded state contains a predominant population that shares the same structural features across all tetraloops studied here and lacks the noncanonical A-G base pair in its loop portion. Further analysis performed with biased trajectories showed that although this competitive misfolded state is not an essential intermediate, it is visited in most of the transitions from unfolded to correctly folded states. Moreover, the tetraloops can transition from this misfolded state to the correctly folded state without requiring extensive unfolding.
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U2 - 10.1021/acs.jpcb.1c08038
DO - 10.1021/acs.jpcb.1c08038
M3 - Article
C2 - 34890201
AN - SCOPUS:85121594262
SN - 1520-6106
VL - 125
SP - 13685
EP - 13695
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 50
ER -