A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States

Zerze, Gül H.; Piaggi, Pablo M.; Debenedetti, Pablo G.

doi:10.1021/acs.jpcb.1c08038

Title: A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States

Abstract

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. Here 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 ismore »« less

Authors:

^[1];

^[1]

Princeton Univ., NJ (United States)

Publication Date:: Fri Dec 10 00:00:00 EST 2021

Research Org.:: Princeton Univ., NJ (United States)

Sponsoring Org.:: USDOE Office of Science (SC); National Science Foundation (NSF)

OSTI Identifier:: 1994991

Grant/Contract Number:: SC0019394; CHE-1856704

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Physical Chemistry. B

Additional Journal Information:: Journal Volume: 125; Journal Issue: 50; Journal ID: ISSN 1520-6106

Publisher:: American Chemical Society

Country of Publication:: United States

Language:: English

Subject:: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; chemical structure; computational chemistry; computer simulations; free energy; genetics

Citation Formats


                    Zerze, Gül H., Piaggi, Pablo M., and Debenedetti, Pablo G. A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States.  United States: N. p., 2021. 
Web.  doi:10.1021/acs.jpcb.1c08038.

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                    Zerze, Gül H., Piaggi, Pablo M., & Debenedetti, Pablo G. A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States.  United States.  https://doi.org/10.1021/acs.jpcb.1c08038

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                    Zerze, Gül H., Piaggi, Pablo M., and Debenedetti, Pablo G. Fri .  
"A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States".  United States.  https://doi.org/10.1021/acs.jpcb.1c08038.  https://www.osti.gov/servlets/purl/1994991.

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@article{osti_1994991,

  title        = {A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States},

  author       = {Zerze, Gül H. and Piaggi, Pablo M. and Debenedetti, Pablo G.},

  abstractNote = {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. Here 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.},

  doi          = {10.1021/acs.jpcb.1c08038},

  journal      = {Journal of Physical Chemistry. B},

  number       = 50,

  volume       = 125,

  place        = {United States},

  year         = {Fri Dec 10 00:00:00 EST 2021},

  month        = {Fri Dec 10 00:00:00 EST 2021}

}

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Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1–3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients andmore »« less
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https://doi.org/10.1063/1.5019939

Full Text Available
RNA Tertiary Interactions Mediate Native Collapse of a Bacterial Group I Ribozyme

Journal Article Chauhan, Seema ; Caliskan, Gokhan ; Briber, Robert M ; ... - J. Mol. Biol.

Large RNAs collapse into compact intermediates in the presence of counterions before folding to the native state. We previously found that collapse of a bacterial group I ribozyme correlates with the formation of helices within the ribozyme core, but occurs at Mg{sup 2+} concentrations too low to support stable tertiary structure and catalytic activity. Here, using small-angle X-ray scattering, we show that Mg{sup 2+}-induced collapse is a cooperative folding transition that can be fit by a two-state model. The Mg{sup 2+} dependence of collapse is similar to the Mg{sup 2+} dependence of helix assembly measured by partial ribonuclease T{sub 1}more »« less

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Title: A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States

Abstract

Citation Formats

RNA Chaperones and the RNA Folding Problem journal, September 1995

Constant pressure molecular dynamics for molecular systems journal, December 1983

Self-splicing RNA: Autoexcision and autocyclization of the ribosomal RNA intervening sequence of tetrahymena journal, November 1982

Folding of RNA involves parallel pathways journal, October 1997

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

Base-stacking and base-pairing contributions into thermal stability of the DNA double helix journal, January 2006

Free-energy landscape of a hyperstable RNA tetraloop journal, May 2016

RNA folding pathways in stop motion journal, April 2016

Exposing the kinetic traps in RNA folding journal, June 1999

Free Energy Landscape of GAGA and UUCG RNA Tetraloops journal, September 2016

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

RNA force field with accuracy comparable to state-of-the-art protein force fields journal, January 2018

Recognition of Planar and Nonplanar Ligands in the Malachite Green-RNA Aptamer Complex journal, December 2003

Isolation of new ribozymes from a large pool of random sequences [see comment] journal, September 1993

How to understand atomistic molecular dynamics simulations of RNA and protein-RNA complexes?: Atomistic molecular dynamics simulations of RNA and protein-RNA complexes journal, November 2016

Mapping the Universe of RNA Tetraloop Folds journal, July 2017

Architecture of ribosomal RNA: constraints on the sequence of "tetra-loops". journal, November 1990

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

Tertiary Motifs in RNA Structure and Folding journal, August 1999

Free Energy Profile of RNA Hairpins: A Molecular Dynamics Simulation Study journal, February 2010

Promoting transparency and reproducibility in enhanced molecular simulations journal, July 2019

Involvement of a GNRA tetraloop in long-range RNA tertiary interactions journal, March 1994

Exceptionally Stable Nucleic Acid Hairpins journal, June 1995

Fine-Tuning of the AMBER RNA Force Field with a New Term Adjusting Interactions of Terminal Nucleotides journal, May 2020

All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins † journal, April 1998

Native contacts determine protein folding mechanisms in atomistic simulations journal, October 2013

Improving the Performance of the Amber RNA Force Field by Tuning the Hydrogen-Bonding Interactions journal, March 2019

Structural Motifs in RNA journal, June 1999

Structural Insight into RNA Hairpin Folding Intermediates journal, July 2008

PLUMED 2: New feathers for an old bird journal, February 2014

Equilibrium conformational dynamics in an RNA tetraloop from massively parallel molecular dynamics journal, March 2010

Crystal Structure of a Group I Ribozyme Domain: Principles of RNA Packing journal, September 1996

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

Empirical Corrections to the Amber RNA Force Field with Target Metadynamics journal, May 2016

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

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

CUUCGG hairpins: extraordinarily stable RNA secondary structures associated with various biochemical processes. journal, March 1988

Insights into RNA structure and function from genome-wide studies journal, May 2014

Free-Energy Landscape for β Hairpin Folding from Combined Parallel Tempering and Metadynamics journal, October 2006

A molecular dynamics method for simulations in the canonical ensemble journal, June 1984

Structural features that give rise to the unusual stability of RNA hairpins containing GNRA loops journal, July 1991

Loop and stem dynamics during RNA hairpin folding and unfolding journal, October 2010

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

GROMACS: A message-passing parallel molecular dynamics implementation journal, September 1995

Conformational ensembles of RNA oligonucleotides from integrating NMR and molecular simulations journal, May 2018

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

Well-Tempered Metadynamics: A Smoothly Converging and Tunable Free-Energy Method journal, January 2008

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

Quality Threshold Clustering of Molecular Dynamics: A Word of Caution journal, September 2019

The molecular configuration of deoxyribonucleic acid journal, April 1960

Enhanced Sampling in the Well-Tempered Ensemble journal, May 2010

The Paradoxical Behavior of a Highly Structured Misfolded Intermediate in RNA Folding journal, October 2006

Dynamics of the RNA Hairpin GNRA Tetraloop † journal, April 2000

Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies journal, August 2016

Protein Folding and Ligand-Enzyme Binding from Bias-Exchange Metadynamics Simulations journal, January 2012

Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/γ Conformers journal, June 2007

Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins journal, November 2010

Folding intermediates of a self-splicing RNA: mispairing of the catalytic core journal, July 1998

Polymorphic transitions in single crystals: A new molecular dynamics method journal, December 1981

Integrating NMR and simulations reveals motions in the UUCG tetraloop journal, May 2020

Fitting Corrections to an RNA Force Field Using Experimental Data journal, April 2019

Balance between α and β Structures in Ab Initio Protein Folding journal, June 2010

A Time-Independent Free Energy Estimator for Metadynamics journal, July 2014

Canonical dynamics: Equilibrium phase-space distributions journal, March 1985

Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles journal, August 2011

Geometric deep learning of RNA structure journal, August 2021

Visualizing transient low-populated structures of RNA journal, October 2012

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

Peptide Folding: When Simulation Meets Experiment journal, January 1999

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

Thermodynamics of DNA Hybridization from Atomistic Simulations journal, January 2021

A smooth particle mesh Ewald method journal, November 1995

The mechanism of RNA base fraying: Molecular dynamics simulations analyzed with core-set Markov state models journal, April 2019

The Ribosome Is a Ribozyme journal, August 2000

Revised AMBER Parameters for Bioorganic Phosphates journal, October 2012

Escaping free-energy minima journal, September 2002

Hierarchy and Dynamics of rna Folding journal, June 1997

RNA Chaperones and the RNA Folding Problem
journal, September 1995

Constant pressure molecular dynamics for molecular systems
journal, December 1983

Self-splicing RNA: Autoexcision and autocyclization of the ribosomal RNA intervening sequence of tetrahymena
journal, November 1982

Folding of RNA involves parallel pathways
journal, October 1997

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

Base-stacking and base-pairing contributions into thermal stability of the DNA double helix
journal, January 2006

Free-energy landscape of a hyperstable RNA tetraloop
journal, May 2016

RNA folding pathways in stop motion
journal, April 2016

Exposing the kinetic traps in RNA folding
journal, June 1999

Free Energy Landscape of GAGA and UUCG RNA Tetraloops
journal, September 2016

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

RNA force field with accuracy comparable to state-of-the-art protein force fields
journal, January 2018

Recognition of Planar and Nonplanar Ligands in the Malachite Green-RNA Aptamer Complex
journal, December 2003

Isolation of new ribozymes from a large pool of random sequences [see comment]
journal, September 1993

How to understand atomistic molecular dynamics simulations of RNA and protein-RNA complexes?: Atomistic molecular dynamics simulations of RNA and protein-RNA complexes
journal, November 2016

Mapping the Universe of RNA Tetraloop Folds
journal, July 2017

Architecture of ribosomal RNA: constraints on the sequence of "tetra-loops".
journal, November 1990

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

Tertiary Motifs in RNA Structure and Folding
journal, August 1999

Free Energy Profile of RNA Hairpins: A Molecular Dynamics Simulation Study
journal, February 2010

Promoting transparency and reproducibility in enhanced molecular simulations
journal, July 2019

Involvement of a GNRA tetraloop in long-range RNA tertiary interactions
journal, March 1994

Exceptionally Stable Nucleic Acid Hairpins
journal, June 1995

Fine-Tuning of the AMBER RNA Force Field with a New Term Adjusting Interactions of Terminal Nucleotides
journal, May 2020

All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins ^†
journal, April 1998

Native contacts determine protein folding mechanisms in atomistic simulations
journal, October 2013

Improving the Performance of the Amber RNA Force Field by Tuning the Hydrogen-Bonding Interactions
journal, March 2019

Structural Motifs in RNA
journal, June 1999

Structural Insight into RNA Hairpin Folding Intermediates
journal, July 2008

PLUMED 2: New feathers for an old bird
journal, February 2014

Equilibrium conformational dynamics in an RNA tetraloop from massively parallel molecular dynamics
journal, March 2010

Crystal Structure of a Group I Ribozyme Domain: Principles of RNA Packing
journal, September 1996

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

Empirical Corrections to the Amber RNA Force Field with Target Metadynamics
journal, May 2016

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

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

CUUCGG hairpins: extraordinarily stable RNA secondary structures associated with various biochemical processes.
journal, March 1988

Insights into RNA structure and function from genome-wide studies
journal, May 2014

Free-Energy Landscape for β Hairpin Folding from Combined Parallel Tempering and Metadynamics
journal, October 2006

A molecular dynamics method for simulations in the canonical ensemble
journal, June 1984

Structural features that give rise to the unusual stability of RNA hairpins containing GNRA loops
journal, July 1991

Loop and stem dynamics during RNA hairpin folding and unfolding
journal, October 2010

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

GROMACS: A message-passing parallel molecular dynamics implementation
journal, September 1995

Conformational ensembles of RNA oligonucleotides from integrating NMR and molecular simulations
journal, May 2018

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

Well-Tempered Metadynamics: A Smoothly Converging and Tunable Free-Energy Method
journal, January 2008

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

Quality Threshold Clustering of Molecular Dynamics: A Word of Caution
journal, September 2019

The molecular configuration of deoxyribonucleic acid
journal, April 1960

Enhanced Sampling in the Well-Tempered Ensemble
journal, May 2010

The Paradoxical Behavior of a Highly Structured Misfolded Intermediate in RNA Folding
journal, October 2006

Dynamics of the RNA Hairpin GNRA Tetraloop ^†
journal, April 2000

Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies
journal, August 2016

Protein Folding and Ligand-Enzyme Binding from Bias-Exchange Metadynamics Simulations
journal, January 2012

Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/γ Conformers
journal, June 2007

Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins
journal, November 2010

Folding intermediates of a self-splicing RNA: mispairing of the catalytic core
journal, July 1998

Polymorphic transitions in single crystals: A new molecular dynamics method
journal, December 1981

Integrating NMR and simulations reveals motions in the UUCG tetraloop
journal, May 2020

Fitting Corrections to an RNA Force Field Using Experimental Data
journal, April 2019

Balance between α and β Structures in Ab Initio Protein Folding
journal, June 2010

A Time-Independent Free Energy Estimator for Metadynamics
journal, July 2014

Canonical dynamics: Equilibrium phase-space distributions
journal, March 1985

Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles
journal, August 2011

Geometric deep learning of RNA structure
journal, August 2021

Visualizing transient low-populated structures of RNA
journal, October 2012

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

Peptide Folding: When Simulation Meets Experiment
journal, January 1999

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

Thermodynamics of DNA Hybridization from Atomistic Simulations
journal, January 2021

A smooth particle mesh Ewald method
journal, November 1995

The mechanism of RNA base fraying: Molecular dynamics simulations analyzed with core-set Markov state models
journal, April 2019

The Ribosome Is a Ribozyme
journal, August 2000

Revised AMBER Parameters for Bioorganic Phosphates
journal, October 2012

Escaping free-energy minima
journal, September 2002

Hierarchy and Dynamics of rna Folding
journal, June 1997

A boundary correction algorithm for metadynamics in multiple dimensions
journal, August 2013

Enhanced Conformational Sampling Using Replica Exchange with Collective-Variable Tempering
journal, February 2015

Water Dispersion Interactions Strongly Influence Simulated Structural Properties of Disordered Protein States
journal, April 2015