DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Free-energy landscape of a hyperstable RNA tetraloop

Abstract

In this paper, we report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the free-energy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the left-handed Z-RNA. Finally, our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.

Authors:
 [1];  [2];  [3]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Rensselaer Polytechnic Inst., Troy, NY (United States). Dept. of Biological Sciences
  2. Univ. at Albany, Albany, NY (United States). Dept. of Chemistry
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Rensselaer Polytechnic Inst., Troy, NY (United States). Dept. of Physics, Applied Physics, and Astronomy
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; LANL Laboratory Directed Research and Development (LDRD) Program; National Science Foundation (NSF); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1457303
Report Number(s):
LA-UR-15-28937
Journal ID: ISSN 0027-8424
Grant/Contract Number:  
AC52-06NA25396; MCB-137078; MCB-1050906; 5T32GM067545-08/9
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 24; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 74 ATOMIC AND MOLECULAR PHYSICS; Biological Science

Citation Formats

Miner, Jacob C., Chen, Alan A., and Garcia, Angel E. Free-energy landscape of a hyperstable RNA tetraloop. United States: N. p., 2016. Web. doi:10.1073/pnas.1603154113.
Miner, Jacob C., Chen, Alan A., & Garcia, Angel E. Free-energy landscape of a hyperstable RNA tetraloop. United States. https://doi.org/10.1073/pnas.1603154113
Miner, Jacob C., Chen, Alan A., and Garcia, Angel E. Fri . "Free-energy landscape of a hyperstable RNA tetraloop". United States. https://doi.org/10.1073/pnas.1603154113. https://www.osti.gov/servlets/purl/1457303.
@article{osti_1457303,
title = {Free-energy landscape of a hyperstable RNA tetraloop},
author = {Miner, Jacob C. and Chen, Alan A. and Garcia, Angel E.},
abstractNote = {In this paper, we report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the free-energy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the left-handed Z-RNA. Finally, our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.},
doi = {10.1073/pnas.1603154113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 24,
volume = 113,
place = {United States},
year = {Fri May 27 00:00:00 EDT 2016},
month = {Fri May 27 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 36 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Remarkable morphological variability of a common RNA folding motif: the GNRATetraloop-receptor interaction 1 1Edited by D. E. Draper
journal, February 1997

  • Abramovitz, Dana L.; Pyle, Anna Marie
  • Journal of Molecular Biology, Vol. 266, Issue 3
  • DOI: 10.1006/jmbi.1996.0810

Rearrangement of Partially Ordered Stacked Conformations Contributes to the Rugged Energy Landscape of a Small RNA Hairpin
journal, October 2008

  • Stancik, Aaron L.; Brauns, Eric B.
  • Biochemistry, Vol. 47, Issue 41
  • DOI: 10.1021/bi801170c

Parameters of Monovalent Ions in the AMBER-99 Forcefield:  Assessment of Inaccuracies and Proposed Improvements
journal, October 2007

  • Chen, Alan A.; Pappu, Rohit V.
  • The Journal of Physical Chemistry B, Vol. 111, Issue 41
  • DOI: 10.1021/jp0765392

Protein folded states are kinetic hubs
journal, June 2010

  • Bowman, G. R.; Pande, V. S.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 24
  • DOI: 10.1073/pnas.1003962107

Characterization of RNA hairpin loop stability
journal, January 1988


Simulation of the Pressure and Temperature Folding/Unfolding Equilibrium of a Small RNA Hairpin
journal, January 2008

  • Garcia, Angel E.; Paschek, Dietmar
  • Journal of the American Chemical Society, Vol. 130, Issue 3
  • DOI: 10.1021/ja074191i

Salt-induced co-operative conformational change of a synthetic DNA: Equilibrium and kinetic studies with poly(dG-dC)
journal, June 1972


A Network of Heterogeneous Hydrogen Bonds in GNRA Tetraloops
journal, December 1996

  • Jucker, Fiona M.; Heus, Hans A.; Yip, Ping F.
  • Journal of Molecular Biology, Vol. 264, Issue 5
  • DOI: 10.1006/jmbi.1996.0690

GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation
journal, February 2008

  • Hess, Berk; Kutzner, Carsten; van der Spoel, David
  • Journal of Chemical Theory and Computation, Vol. 4, Issue 3
  • DOI: 10.1021/ct700301q

Fast Folding of an RNA Tetraloop on a Rugged Energy Landscape Detected by a Stacking-Sensitive Probe
journal, September 2009


Structure of an unusually stable RNA hairpin
journal, April 1991

  • Varani, Gabriele; Cheong, Chaejoon; Tinoco, Ignacio
  • Biochemistry, Vol. 30, Issue 13
  • DOI: 10.1021/bi00227a016

Computational Study of the Stability of the Miniprotein Trp-Cage, the GB1 β-Hairpin, and the AK16 Peptide, under Negative Pressure
journal, March 2014

  • Hatch, Harold W.; Stillinger, Frank H.; Debenedetti, Pablo G.
  • The Journal of Physical Chemistry B, Vol. 118, Issue 28
  • DOI: 10.1021/jp410651u

Comparison of simple potential functions for simulating liquid water
journal, July 1983

  • Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
  • The Journal of Chemical Physics, Vol. 79, Issue 2
  • DOI: 10.1063/1.445869

A-Z-RNA conformational changes effected by high pressure
journal, January 1994

  • Krzyżaniak, Andrzej; Barciszewski, Jan; Fürste, Jens Peter
  • International Journal of Biological Macromolecules, Vol. 16, Issue 3
  • DOI: 10.1016/0141-8130(94)90044-2

Highly sampled tetranucleotide and tetraloop motifs enable evaluation of common RNA force fields
journal, June 2015


Right- and left-handed (Z) helical conformations of the hairpin d(C-G)5T4(C-G)5 monomer and dimer
journal, October 1985

  • Germann, Markus W.; Schoenwaelder, Karl Heinz; van de Sande, Johan H.
  • Biochemistry, Vol. 24, Issue 21
  • DOI: 10.1021/bi00342a002

Mfold web server for nucleic acid folding and hybridization prediction
journal, July 2003


Mechanical unfolding of RNA hairpins
journal, March 2005

  • Hyeon, C.; Thirumalai, D.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 19
  • DOI: 10.1073/pnas.0408314102

A thermodynamic study of unusually stable RNA and DNA hairpins
journal, January 1991

  • Antao, Vincent P.; Lai, Sandy Y.; Tinoco, Ignacio
  • Nucleic Acids Research, Vol. 19, Issue 21
  • DOI: 10.1093/nar/19.21.5901

Extensive Backbone Dynamics in the GCAA RNA Tetraloop Analyzed Using 13 C NMR Spin Relaxation and Specific Isotope Labeling
journal, December 2008

  • Johnson, James E.; Hoogstraten, Charles G.
  • Journal of the American Chemical Society, Vol. 130, Issue 49
  • DOI: 10.1021/ja805759z

Structural Insight into RNA Hairpin Folding Intermediates
journal, July 2008

  • Bowman, Gregory R.; Huang, Xuhui; Yao, Yuan
  • Journal of the American Chemical Society, Vol. 130, Issue 30
  • DOI: 10.1021/ja8032857

Free-Energy Landscape of RNA Hairpins Constructed via Dihedral Angle Principal Component Analysis
journal, December 2009

  • Riccardi, Laura; Nguyen, Phuong H.; Stock, Gerhard
  • The Journal of Physical Chemistry B, Vol. 113, Issue 52
  • DOI: 10.1021/jp9076036

A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules
journal, May 1995

  • Cornell, Wendy D.; Cieplak, Piotr; Bayly, Christopher I.
  • Journal of the American Chemical Society, Vol. 117, Issue 19
  • DOI: 10.1021/ja00124a002

Direct Revelation of Multiple Conformations in RNA by Femtosecond Dynamics
journal, April 2007

  • Zhao, Liang; Xia, Tianbing
  • Journal of the American Chemical Society, Vol. 129, Issue 14
  • DOI: 10.1021/ja068391q

On the Stability of Double Stranded Nucleic Acids
journal, September 2001

  • Dubins, David N.; Lee, Adrian; Macgregor, Robert B.
  • Journal of the American Chemical Society, Vol. 123, Issue 38
  • DOI: 10.1021/ja004309u

Exploring the Energy Landscape of a Small RNA Hairpin
journal, February 2006

  • Ma, Hairong; Proctor, David J.; Kierzek, Elzbieta
  • Journal of the American Chemical Society, Vol. 128, Issue 5
  • DOI: 10.1021/ja0553856

Molecular structure of a left-handed double helical DNA fragment at atomic resolution
journal, December 1979

  • Wang, Andrew H. -J.; Quigley, Gary J.; Kolpak, Francis J.
  • Nature, Vol. 282, Issue 5740
  • DOI: 10.1038/282680a0

Salt- and solvent-dependent conformational transitions of ribo-CGCGCG duplex
journal, August 1985

  • Adamiak, Ryszard W.; Gałat, Andrzej; Skalski, Bohdan
  • Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, Vol. 825, Issue 4
  • DOI: 10.1016/0167-4781(85)90060-0

Multiple Probes are Required to Explore and Control the Rugged Energy Landscape of RNA Hairpins
journal, February 2008

  • Hyeon, Changbong; Thirumalai, D.
  • Journal of the American Chemical Society, Vol. 130, Issue 5
  • DOI: 10.1021/ja0771641

Solution structure of an unusually stable RNA hairpin, 5GGAC(UUCG)GUCC
journal, August 1990

  • Cheong, Chaejoon; Varani, Gabriele; Tinoco, Ignacio
  • Nature, Vol. 346, Issue 6285
  • DOI: 10.1038/346680a0

Canonical sampling through velocity rescaling
journal, January 2007

  • Bussi, Giovanni; Donadio, Davide; Parrinello, Michele
  • The Journal of Chemical Physics, Vol. 126, Issue 1
  • DOI: 10.1063/1.2408420

High-resolution reversible folding of hyperstable RNA tetraloops using molecular dynamics simulations
journal, September 2013

  • Chen, A. A.; Garcia, A. E.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 42
  • DOI: 10.1073/pnas.1309392110

Extraordinarily stable mini-hairpins: electrophoretical and thermal properties of the various sequence variants of d(GCFAAAGC)and their effect on DNA sequencing
journal, January 1992

  • Hirao, Ichiro; Nishimura, Yoshifumi; Tagawa, Yon-ichi
  • Nucleic Acids Research, Vol. 20, Issue 15
  • DOI: 10.1093/nar/20.15.3891

Structures, Kinetics, Thermodynamics, and Biological Functions of RNA Hairpins
journal, May 2008


Insights into Stability and Folding of GNRA and UNCG Tetraloops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics
journal, July 2015

  • Haldar, Susanta; Kührová, Petra; Banáš, Pavel
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 8
  • DOI: 10.1021/acs.jctc.5b00010

Thermodynamic parameters for loop formation in RNA and DNA hairpin tetraloops
journal, January 1992

  • Antao, Vincent P.; Tinoco, Ignacio
  • Nucleic Acids Research, Vol. 20, Issue 4
  • DOI: 10.1093/nar/20.4.819

Molecular dynamics with coupling to an external bath
journal, October 1984

  • Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.
  • The Journal of Chemical Physics, Vol. 81, Issue 8
  • DOI: 10.1063/1.448118

Dynamics of the RNA Hairpin GNRA Tetraloop
journal, April 2000

  • Menger, Marcus; Eckstein, Fritz; Porschke, Dietmar
  • Biochemistry, Vol. 39, Issue 15
  • DOI: 10.1021/bi992297n

How RNA folds
journal, October 1999

  • Tinoco, Ignacio; Bustamante, Carlos
  • Journal of Molecular Biology, Vol. 293, Issue 2
  • DOI: 10.1006/jmbi.1999.3001

Z-DNA: the long road to biological function
journal, July 2003

  • Rich, Alexander; Zhang, Shuguang
  • Nature Reviews Genetics, Vol. 4, Issue 7
  • DOI: 10.1038/nrg1115

Energetics of Nucleic Acid Stability:  The Effect of Δ C P
journal, December 2004

  • Tikhomirova, Anna; Taulier, Nicolas; Chalikian, Tigran V.
  • Journal of the American Chemical Society, Vol. 126, Issue 50
  • DOI: 10.1021/ja046387d

Mechanical Unfolding of RNA: From Hairpins to Structures with Internal Multiloops
journal, February 2007


Classification and energetics of the base-phosphate interactions in RNA
journal, June 2009

  • Zirbel, Craig L.; Šponer, Judit E.; Šponer, Jiri
  • Nucleic Acids Research, Vol. 37, Issue 15
  • DOI: 10.1093/nar/gkp468

Replica-exchange molecular dynamics method for protein folding
journal, November 1999


Computer Folding of RNA Tetraloops? Are We There Yet?
journal, March 2013

  • Kührová, Petra; Banáš, Pavel; Best, Robert B.
  • Journal of Chemical Theory and Computation, Vol. 9, Issue 4
  • DOI: 10.1021/ct301086z

DNA folding and melting observed in real time redefine the energy landscape
journal, January 2007

  • Ma, Hairong; Wan, Chaozhi; Wu, Aiguo
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 3
  • DOI: 10.1073/pnas.0610028104

RNA simulations: probing hairpin unfolding and the dynamics of a GNRA tetraloop 1 1Edited by J. Dovdna
journal, April 2002

  • Sorin, Eric J.; Engelhardt, Mark A.; Herschlag, Daniel
  • Journal of Molecular Biology, Vol. 317, Issue 4
  • DOI: 10.1006/jmbi.2002.5447

Conformation and dynamics of a left-handed Z-DNA hairpin: studies of d(CGCGCGTTTTCGCGCG) in solution
journal, April 1989

  • Benight, Albert S.; Wang, Yusen; Amaratunga, Mohan
  • Biochemistry, Vol. 28, Issue 8
  • DOI: 10.1021/bi00434a030

A smooth particle mesh Ewald method
journal, November 1995

  • Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.
  • The Journal of Chemical Physics, Vol. 103, Issue 19
  • DOI: 10.1063/1.470117

Dihedral angle principal component analysis of molecular dynamics simulations
journal, June 2007

  • Altis, Alexandros; Nguyen, Phuong H.; Hegger, Rainer
  • The Journal of Chemical Physics, Vol. 126, Issue 24
  • DOI: 10.1063/1.2746330

Validation of molecular simulation by comparison with experiment: Rotational reorientation of tryptophan in water
journal, February 1999

  • Daura, Xavier; Suter, Raymond; van Gunsteren, Wilfred F.
  • The Journal of Chemical Physics, Vol. 110, Issue 6
  • DOI: 10.1063/1.477900

‘Z-RNA’—a left-handed RNA double helix
journal, October 1984

  • Hall, Kathleen; Cruz, Phillip; Tinoco, Ignacio
  • Nature, Vol. 311, Issue 5986
  • DOI: 10.1038/311584a0

A Left-Handed RNA Double Helix Bound by the Zα Domain of the RNA-Editing Enzyme ADAR1
journal, April 2007


High salt solution structure of a left-handed RNA double helix
journal, July 2004


Insights into Nucleic Acid Conformational Dynamics from Massively Parallel Stochastic Simulations
journal, August 2003


Monte Carlo Simulations
book, September 2002


Morphological and genetic characterization of the first Isospora species (I. lugensae n. sp.) from a Kerguelen petrel (Lugensa brevirostris)
journal, January 2021


Works referencing / citing this record:

Perspective: Identification of collective variables and metastable states of protein dynamics
journal, October 2018

  • Sittel, Florian; Stock, Gerhard
  • The Journal of Chemical Physics, Vol. 149, Issue 15
  • DOI: 10.1063/1.5049637

Emergency Services of Viral RNAs: Repair and Remodeling
journal, March 2018

  • Agol, Vadim I.; Gmyl, Anatoly P.
  • Microbiology and Molecular Biology Reviews, Vol. 82, Issue 2
  • DOI: 10.1128/mmbr.00067-17

Effect of GCAA stabilizing loops on three- and four-way intramolecular junctions
journal, January 2018

  • Carr, Carolyn E.; Marky, Luis A.
  • Physical Chemistry Chemical Physics, Vol. 20, Issue 7
  • DOI: 10.1039/c7cp08329g

Mechanistic role of nucleobases in self-cleavage catalysis of hairpin ribozyme at ambient versus high-pressure conditions
journal, January 2018

  • Kumar, Narendra; Marx, Dominik
  • Physical Chemistry Chemical Physics, Vol. 20, Issue 32
  • DOI: 10.1039/c8cp03142h

Probing the operability regime of an engineered ribocomputing unit in terms of dynamic range maintenance with extracellular changes and time
journal, March 2020

  • Montagud-Martínez, Roser; Ventura, Jordi; Ballesteros-Garrido, Rafael
  • Journal of Biological Engineering, Vol. 14, Issue 1
  • DOI: 10.1186/s13036-020-00234-5

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop
journal, June 2018

  • Miner, Jacob Carlson; García, Angel Enrique
  • The Journal of Chemical Physics, Vol. 148, Issue 22
  • DOI: 10.1063/1.5019939

Pressure modulates the self-cleavage step of the hairpin ribozyme
journal, March 2017

  • Schuabb, Caroline; Kumar, Narendra; Pataraia, Salome
  • Nature Communications, Vol. 8, Issue 1
  • DOI: 10.1038/ncomms14661

In silico direct folding of thrombin-binding aptamer G-quadruplex at all-atom level
journal, November 2017

  • Yang, Changwon; Kulkarni, Mandar; Lim, Manho
  • Nucleic Acids Research, Vol. 45, Issue 22
  • DOI: 10.1093/nar/gkx1079