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RNA and its ionic cloud: solution scattering experiments and atomically detailed simulations.
Biophys J. 2012 Feb 22; 102(4):819-28
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29 May 2012
Confirmation, New Finding, Technical Advance
DOI: 10.3410/f.716197902.791652807
RNA molecules possess diverse functions related to gene regulation and expression, which suggests great potential for therapeutic use and gene regulation. Metal ions are crucial to RNA structure, e.g. for folding and stability, and they are involved in a wide variety of biological functions. This paper...Continue reading
RNA molecules possess diverse functions related to gene regulation and expression, which suggests great potential for therapeutic use and gene regulation. Metal ions are crucial to RNA structure, e.g. for folding and stability, and they are involved in a wide variety of biological functions. This paper reports a complementary approach between anomalous small-angle X-ray scattering (ASAXS) and all-atom molecular dynamics (MD) simulations to obtain a better molecular picture of the RNA in ionic solution.
The study focused on counter-ions (and co-ions) around relatively short 25-basepair RNA duplexes. The ASAXS showed that the numbers of excess Rb+ and Sr2+ at 0.1M of bulk concentration were ~35±3 and ~19.2±1.7 per duplex, respectively, which are in good accordance with calculations employing all-atom replica-exchange MD with explicit ions and water. In addition, the results from the ASAXS and the MD simulations agreed well for the spatial distributions of Rb+ and Sr2+. More importantly, the MD simulations provided further useful insights. For monovalent ions, the neutralization by monovalent ions (e.g. Rb+ and Na+) was shown to be independent of the ion size. However, it was found that divalent ions can bind tightly and specifically to well-defined sites at the RNA surface and form a more compact ion cloud. The simulations showed that Mg2+ binds more tightly to RNA than Sr2+ and the radial distribution function of Mg2+ is dramatically different from those of Na+, Rb+, and Sr2+, although all ions are nearly identical at short distances to RNA. Furthermore, it was shown that, as the salt concentration increases, more co-ions are depleted from the RNA proximity, whereas the absolute number of co-ions near the RNA increases.
Interestingly, the MD simulations showed co-localizations of co-ions with the peak positions of counter-ions, which may not be obtained from nonlinear Poisson Boltzmann (NLPB) models in general. The MD simulations were extended to study pseudoknot RNA tertiary structure interactions in the vicinity of the folded state where similar good agreement with the ASAXS was observed. This complementary combination between the ASAXS and the MD simulations can bring better and more detailed pictures of the RNA-counter-ion systems required to understand the folding and function of RNA.
The study focused on counter-ions (and co-ions) around relatively short 25-basepair RNA duplexes. The ASAXS showed that the numbers of excess Rb+ and Sr2+ at 0.1M of bulk concentration were ~35±3 and ~19.2±1.7 per duplex, respectively, which are in good accordance with calculations employing all-atom replica-exchange MD with explicit ions and water. In addition, the results from the ASAXS and the MD simulations agreed well for the spatial distributions of Rb+ and Sr2+. More importantly, the MD simulations provided further useful insights. For monovalent ions, the neutralization by monovalent ions (e.g. Rb+ and Na+) was shown to be independent of the ion size. However, it was found that divalent ions can bind tightly and specifically to well-defined sites at the RNA surface and form a more compact ion cloud. The simulations showed that Mg2+ binds more tightly to RNA than Sr2+ and the radial distribution function of Mg2+ is dramatically different from those of Na+, Rb+, and Sr2+, although all ions are nearly identical at short distances to RNA. Furthermore, it was shown that, as the salt concentration increases, more co-ions are depleted from the RNA proximity, whereas the absolute number of co-ions near the RNA increases.
Interestingly, the MD simulations showed co-localizations of co-ions with the peak positions of counter-ions, which may not be obtained from nonlinear Poisson Boltzmann (NLPB) models in general. The MD simulations were extended to study pseudoknot RNA tertiary structure interactions in the vicinity of the folded state where similar good agreement with the ASAXS was observed. This complementary combination between the ASAXS and the MD simulations can bring better and more detailed pictures of the RNA-counter-ion systems required to understand the folding and function of RNA.
Disclosures
None declared
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Baker N and Chun J: F1000Prime Recommendation of [Kirmizialtin S et al., Biophys J 2012, 102(4):819-28]. In F1000Prime, 29 May 2012; DOI: 10.3410/f.716197902.791652807. F1000Prime.com/716197902#eval791652807
F1000Prime Recommendations, Dissents and Comments for [Kirmizialtin S et al., Biophys J 2012, 102(4):819-28]. In F1000Prime, 19 May 2013; F1000Prime.com/716197902
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RNA molecules play critical roles in many cellular processes. Traditionally viewed as genetic messengers, RNA molecules were recently discovered to have diverse functions related to gene regulation and expression. RNA also has great potential as a therapeutic and a tool for further investigation of gene regulation. Metal ions are an integral part of RNA structure and should be considered in any experimental or theoretical study of RNA. Here, we report a multidisciplinary approach that combines anomalous small-angle x-ray scattering and molecular-dynamics (MD) simulations with explicit solvent and ions around RNA. From experiment and simulation results, we find excellent agreement in the number and distribution of excess monovalent and divalent ions around a short RNA duplex. Although similar agreement can be obtained from a continuum description of the solvent and mobile ions (by solving the Poisson-Boltzmann equation and accounting for finite ion size), the use of MD is easily extended to flexible RNA systems with thermal fluctuations. Therefore, we also model a short RNA pseudoknot and find good agreement between the MD results and the experimentally derived solution structures. Surprisingly, both deviate from crystal structure predictions. These favorable comparisons of experiment and simulations encourage work on RNA in all-atom dynamic models.
Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bpj.2012.01.013
PMID: 22385853
