scholarly journals Folding RNA in mixtures of monovalent and divalent cations: Theory and simulations

2019 ◽  
Author(s):  
Hung T. Nguyen ◽  
Naoto Hori ◽  
D. Thirumalai
Keyword(s):  
Excellent Agreement ◽  
Rna Folding ◽  
Divalent Cations ◽  
Coarse Grained ◽  
Free Energies ◽  
Divalent Ions ◽  
Rna Molecules ◽  
Monovalent Ions ◽  
The Impact ◽  
Phosphate Groups

RNA molecules cannot fold in the absence of counter ions. Experiments are typically performed in the presence of monovalent and divalent cations. How to treat the impact of a solution containing a mixture of both ion types on RNA folding has remained a challenging problem for decades. By exploiting the large concentration difference between divalent and monovalent ions used in experiments, we develop a theory based on the Reference Interaction Site Model (RISM), which allows us to treat divalent cations explicitly while keeping the implicit screening effect due to monovalent ions. Our theory captures both the inner shell and outer shell coordination of divalent cations to phosphate groups, which we demonstrate is crucial in an accurate calculation of RNA folding thermodynamics. The RISM theory for ion-phosphate interactions when combined with simulations based on a transferable coarse-grained model allows us to accurately predict the folding of several RNA molecules in a mixture containing monovalent and divalent ions. The calculated folding free energies and ion-preferential coefficients for RNA molecules (pseudoknots, a fragment of the ribosomal RNA, and the aptamer domain of the adenine riboswitch) are in excellent agreement with experiments over a wide range of monovalent and divalent ion concentrations. Because the theory is general, it can be readily used to investigate ion and sequence effects on DNA properties.Significance StatementRNA molecules require ions to fold. The problem of how ions of differing sizes and valences drive the folding of RNA molecules is unsolved. Here, we take a major step in its solution by creating a method, based on the theory of polyatomic liquids, to calculate the potential between divalent ions and the phosphate groups. The resulting model, accounting for inner and outer sphere coordination of Mg2+ and Ca2+ to phosphates, when used in coarse-grained molecular simulations predicts folding free energies for a number of RNA molecules in the presence of both divalent and monovalent ions that are in excellent agreement with experiments. The work sets the stage for probing sequence and ion effects on DNA and synthetic polyelectrolytes.

scholarly journals Theory and simulations for RNA folding in mixtures of monovalent and divalent cations

2019 ◽  
Vol 116 (42) ◽  
pp. 21022-21030 ◽  
Author(s):  
Hung T. Nguyen ◽  
Naoto Hori ◽  
D. Thirumalai
Keyword(s):  
Rna Folding ◽  
Divalent Cations ◽  
Coarse Grained ◽  
Concentration Difference ◽  
Rna Molecules ◽  
Site Model ◽  
Monovalent Ions ◽  
Wide Range ◽  
Sequence Effects ◽  
The Impact

RNA molecules cannot fold in the absence of counterions. Experiments are typically performed in the presence of monovalent and divalent cations. How to treat the impact of a solution containing a mixture of both ion types on RNA folding has remained a challenging problem for decades. By exploiting the large concentration difference between divalent and monovalent ions used in experiments, we develop a theory based on the reference interaction site model (RISM), which allows us to treat divalent cations explicitly while keeping the implicit screening effect due to monovalent ions. Our theory captures both the inner shell and outer shell coordination of divalent cations to phosphate groups, which we demonstrate is crucial for an accurate calculation of RNA folding thermodynamics. The RISM theory for ion–phosphate interactions when combined with simulations based on a transferable coarse-grained model allows us to predict accurately the folding of several RNA molecules in a mixture containing monovalent and divalent ions. The calculated folding free energies and ion-preferential coefficients for RNA molecules (pseudoknots, a fragment of the rRNA, and the aptamer domain of the adenine riboswitch) are in excellent agreement with experiments over a wide range of monovalent and divalent ion concentrations. Because the theory is general, it can be readily used to investigate ion and sequence effects on DNA properties.

scholarly journals Ion Condensation onto Ribozyme is Site-Specific and Fold-Dependent

2019 ◽  
Author(s):  
Naoto Hori ◽  
Natalia A. Denesyuk ◽  
D. Thirumalai
Keyword(s):  
Self Assembly ◽  
Divalent Cations ◽  
Coarse Grained ◽  
Nucleotide Position ◽  
Structural Elements ◽  
Rna Molecules ◽  
Low Concentrations ◽  
Monovalent Ions ◽  
Tertiary Interactions ◽  
Phosphate Groups

AbstractThe highly charged RNA molecules, with each phosphate carrying a single negative charge, cannot fold into well-defined architectures with tertiary interactions, in the absence of ions. For ribozymes, divalent cations are known to be more efficient than monovalent ions in driving them to a compact state although often Mg2+ ions are needed for catalytic activity. Therefore, how ions interact with RNA is relevant in understanding RNA folding. It is often thought that the most of the ions are territorially and non-specifically bound to the RNA, as predicted by the counterion condensation (CIC) theory. Here, we show using simulations of Azoarcus ribozyme, based on an accurate coarse-grained Three Site Interaction (TIS) model, with explicit divalent and monovalent cations, that ion condensation is highly specific and depends on the nucleotide position. The regions with high coordination between the phosphate groups and the divalent cations are discernible at very low concentrations when the ribozyme does not form tertiary interactions. Surprisingly, these regions also contain the secondary structural elements that nucleate subsequently in the self-assembly of RNA, implying that ion condensation is determined by the architecture of the folded state. These results are in sharp contrast to interactions of ions (monovalent and divalent) with rigid charged rods in which ion condensation is uniform and position independent. The differences are explained in terms of the dramatic non-monotonic shape fluctuations in the ribozyme as it folds with increasing Mg2+ or Ca2+ concentration.

scholarly journals Charge density of cation determines inner versus outer shell coordination to phosphate in RNA

2020 ◽  
Author(s):  
Hung T. Nguyen ◽  
D. Thirumalai
Keyword(s):  
Charge Density ◽  
Divalent Cations ◽  
Outer Shell ◽  
Divalent Ions ◽  
High Charge Density ◽  
Specific Manner ◽  
Effective Charges ◽  
Modes Of Interaction ◽  
Prevailing View ◽  
Phosphate Groups

Divalent cations are often required to fold RNA, which is a highly charged polyanion. Condensation of ions, such as Mg2+ or Ca2+, in the vicinity of RNA renormalizes the effective charges on the phosphate groups, thus minimizing the intra RNA electrostatic repulsion. The prevailing view is that divalent ions bind diffusively in a non-specific manner. In sharp contrast, we arrive at the exact opposite conclusion using a theory for the interaction of ions with the phosphate groups using RISM theory in conjunction with simulations based on an accurate Three Interaction Site RNA model. The divalent ions bind in a nucleotide-specific manner using either the inner (partially dehydrated) or outer (fully hydrated) shell coordination. The high charge density Mg2+ ion has a preference to bind to the outer shell whereas the opposite is the case for Ca2+. Surprisingly, we find that bridging interactions, involving ions that are coordinated to two or more phosphate groups, play a crucial role in maintaining the integrity of the folded state. Their importance could become increasingly prominent as the size of the RNA increases. Because the modes of interaction of divalent ions with DNA are likely to be similar, we propose that specific inner and outer shell coordination could play a role in DNA condensation, and perhaps genome organization as well.

scholarly journals Theoretical and computational modeling of naturally and artificially modified RNA nucleotides

2021 ◽  
Author(s):  
◽  
Travis Caleb Hurst
Keyword(s):  
3D Structure ◽  
Experimental Information ◽  
Potential Of Mean Force ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Structure Stability ◽  
Rna Molecules ◽  
Parameterization Method ◽  
The Impact ◽  
Structural Ensemble

Ribonucleic acid (RNA) is a polymeric nucleic acid that is crucial for cellular function, regulating gene expression and encoding/decoding protein/DNA molecules. Recent discoveries of diverse functionality in non-coding RNAs have led to unprecedented demand for RNA 3D structure determination. With current technology, general, accurate prediction of 3D structures for large RNAs from the sequence remains computationally intractable. One of the principal challenges arises from the conformational flexibility of RNA, especially in loop/junction regions, which results in a rugged energy landscape. Several strategies exist to overcome this challenge, including incorporation of efficient experimental information and coarse-grained (CG) modeling to improve computational sampling of the structural ensemble. A second challenge is the inclusion of naturally modified derivatives of canonical RNA nucleotides in structure analysis. Most RNA prediction strategies rely upon the canonical nucleotides (adenine (A), uracil (U), guanine (G), and cytosine (C)), ignoring the effects of modified nucleotides on the structure and system dynamics. In general, RNA molecules contain rigid and flexible structural elements, which can be probed using efficient selective 2'-hydroxyl analyzed by primer extension (SHAPE) experiments. SHAPE experiments selectively modify flexible RNA nucleotides and can be processed to produce a characteristic reactivity profile for an RNA molecule that contains structural information. Incorporation of efficient experimental information, such as SHAPE, in predicting RNA 3D structure is highly desirable for overcoming the current knowledge gap between RNA sequence and 3D structure. In the first project, we introduce a physics-based model, the 3D structure-SHAPE relationship (3DSSR) model, to predict the SHAPE reactivity from the structure and show how this model may be used to sieve SHAPE-compatible structures from a pool of low-energy decoys and refine our predictions. In the second project, we compare 3DSSR performance to that of a convolutional neural network (CNN) trained on the SHAPE data and RNA structures, showing that 3DSSR outperforms the CNN given the limited data available. In the third project, we further improve the 3DSSR model, gaining deeper insights into the SHAPE reaction and biases. In the fourth project, we explore the theory underpinning the iterative simulated CG RNA folding model (IsRNA). In establishing the underlying mechanics driving the success of the model, we were able to clarify and improve the parameterization method while expanding the model interpretation, which should broaden application of the method to other biopolymers, such as protein. We found that the parameterization method follows statistical mechanics principles but also has a Bayesian interpretation. Further, we found that the parameterization process can benefit from application of the principle of maximum entropy, which improves simulation and parameterization efficiency. In the fifth project, we investigate the impact of nucleotide modification on the structure and configurational ensemble of RNA molecules using free energy calculations. By applying modifications to a common RNA hairpin, we estimate the impact on the stability of the structural ensemble, identifying specific interactions that drive changes to the potential of mean force (PMF) and showing the context and modification-dependence of the variable alterations to the structure stability.

scholarly journals Elucidation of ion effects on the Thermodynamics of RNA Folding

2018 ◽  
Author(s):  
Natalia A. Denesyuk ◽  
D. Thirumalai
Keyword(s):  
Free Energy ◽  
Single Molecule ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Rna Folding ◽  
Coarse Grained ◽  
Significant Advance ◽  
Rna Molecules ◽  
Ion Effects ◽  
The Difference

AbstractHow ions affect RNA folding thermodynamics and kinetics is an important but a vexing problem that remains unsolved. Experiments have shown that the free energy change, ΔG(c), of RNA upon folding varies with the salt concentration (c) as, ΔG(c) = kc ln c + const, where the coefficient kc is proportional to the difference in the uptake of ions (ion preferential coefficient), ΔΓ, between the folded and unfolded states. We performed simulations of a coarse-grained model, by modeling electrostatic interactions implicitly and with explicit representation of ions, to elucidate the molecular underpinnings of the relationship between folding free energy and ion preferential coefficient. Without any input from experiments, the simulations quantitatively reproduce the heat capacity for the −1 frame shifting pseudoknot (PK) from Beet Western Yellow Virus, thus validating the model. We show that ΔG(c) calculated directly from ΔΓ varies linearly with ln c (c < 0.2M), for a hairpin and the PK, thus demonstrating a molecular link between the two quantities for RNA molecules that undergo substantial conformational changes during folding. Explicit ion simulations also show the linear dependence of ΔG(c) on ln c at all c with kc = 2kBT, except that ΔG(c) values are shifted by about 2 kcal/mol higher than experiments at all salt concentrations. The discrepancy is due to an underestimate the Γ values for both the folded and unfolded states, while giving accurate values for ΔΓ. The predictions for the salt dependence of ΔΓ are amenable to test using single molecule pulling experiments. Our simulations, representing a significant advance in quantitatively describing ion effects in RNA, show that the framework provided here can be used to obtain accurate thermodynamics of RNA folding.

Parameterization of Divalent Cations for Coarse-Grained Simulations

2020 ◽  
Author(s):  
Florencia Klein ◽  
Daniela Cáceres-Rojas ◽  
Monica Carrasco ◽  
Juan Carlos Tapia ◽  
Julio Caballero ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Metal Ions ◽  
Molecular Dynamics Simulations ◽  
Divalent Cations ◽  
Computational Cost ◽  
Data Bank ◽  
Coarse Grained ◽  
Interaction Parameters ◽  
Dynamics Simulations ◽  
Dynamical Description

<p>Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges to achieve an accurate structural and dynamical description of many biological assemblies. This is particularly the case for coarse-grained (CG) models. Although the reduced computational cost of CG methods often makes them the technique of choice for the study of large biomolecular systems, the parameterization of metal ions is still very crude or simply not available for the vast majority of CG- force fields. Here, we show that incorporating statistical data retrieved from the Protein Data Bank (PDB) to set specific Lennard-Jones interactions can produce structurally accurate CG molecular dynamics simulations. Using this simple approach, we provide a set of interaction parameters for Calcium, Magnesium, and Zinc ions, which cover more than 80% of the metal-bound structures reported on the PDB. Simulations performed using the SIRAH force field on several proteins and DNA systems show that using the present approach it is possible to obtain non-bonded interaction parameters that obviate the use of topological constraints. </p>

scholarly journals Impact of tailored water chemistry aqueous ions on foam stability enhancement

2021 ◽  
Author(s):  
Zuhair AlYousef ◽  
Subhash Ayirala ◽  
Majed Almubarak ◽  
Dongkyu Cha
Keyword(s):  
Aqueous Solutions ◽  
Water Chemistry ◽  
Foam Stability ◽  
Chloride Salt ◽  
Foam Generation ◽  
Monovalent Ions ◽  
Injection Water ◽  
Foam Stabilization ◽  
Aqueous Ions ◽  
The Impact

AbstractGenerating strong and stable foam is necessary to achieve in-depth conformance control in the reservoir. Besides other parameters, the chemistry of injection water can significantly impact foam generation and stabilization. The tailored water chemistry was found to have good potential to improve foam stability. The objective of this study is to extensively evaluate the effect of different aqueous ions in the selected tailored water chemistry formulations on foam stabilization. Bulk and dynamic foam experiments were used to evaluate the impact of different tailored water chemistry aqueous ions on foam generation and stabilization. For bulk foam tests, the stability of foams generated using three surfactants and different aqueous ions was analyzed using bottle tests. For dynamic foam experiments, the tests were conducted using a microfluidic device. The results clearly demonstrated that the ionic content of aqueous solutions can significantly affect foam stabilization. The results revealed that the foam stabilization in bulk is different than that in porous media. Depending on the surfactant type, the divalent ions were found to have stronger influence on foam stabilization when compared to monovalent ions. The bulk foam results pointed out that the aqueous solutions containing calcium chloride salt (CaCl2) showed longer foam life with the anionic surfactant and very weak foam with the nonionic surfactant. The solutions with magnesium chloride (MgCl2) and CaCl2 salts displayed higher impact on foam stability in comparison with sodium chloride (NaCl) with the amphoteric alkyl amine surfactant. Less stable foams were generated with aqueous solutions comprising of both magnesium and calcium ions. In the microfluidic model, the solutions containing MgCl2 showed higher resistance to gas flow and subsequently higher mobility reduction factor for the injection gas when compared to those produced using NaCl and CaCl2 salts. This experimental study focusing about the role of different aqueous ions in the injection water on foam could help in better understanding the foam stabilization process. The new knowledge gained can also enable the selection and optimization of the right injection water chemistry and suitable chemicals for foam field applications.

scholarly journals Review of the relationship between aggregates geology and Los Angeles and micro-Deval tests

2021 ◽  
Vol 80 (3) ◽  
pp. 1963-1980
Author(s):  
Solomon Adomako ◽  
Christian John Engelsen ◽  
Rein Terje Thorstensen ◽  
Diego Maria Barbieri
Keyword(s):  
Los Angeles ◽  
Crystal Size ◽  
Grain Shape ◽  
Mechanical Performance ◽  
Pore Space ◽  
Construction Material ◽  
Engineering Properties ◽  
Coarse Grained ◽  
The Impact ◽  
The Relationship

AbstractRock aggregates constitute the enormous volume of inert construction material used around the globe. The petrologic description as igneous, sedimentary, and metamorphic types establishes the intrinsic formation pattern of the parent rock. The engineering properties of these rocks vary due to the differences in the transformation process (e.g. hydrothermal deposits) and weathering effect. The two most common mechanical tests used to investigate the performance of aggregates are the Los Angeles (LA) and micro-Deval (MD) tests. This study reviewed the geological parameters (including mineralogy, grain and crystal size, grain shape, and porosity) and the relationship to Los Angeles and micro-Deval tests. It was found that high content of primary minerals in rocks (e.g. quartz and feldspar) is a significant parameter for performance evaluation. Traces of secondary and accessory minerals also affect the performance of rocks, although in many cases it is based on the percentage. Furthermore, some studies showed that the effect of mineralogic composition on mechanical strength is not sufficient to draw final conclusions of mechanical performance; therefore, the impact of other textural characteristics should be considered. The disposition of grain size and crystal size (e.g. as result of lithification) showed that rocks composed of fine-grain textural composition of ≤ 1 mm enhanced fragmentation and wear resistance than medium and coarse grained (≥ 1 mm). The effect of grain shape was based on convex and concave shapes and flat and elongated apexes of tested samples. The equidimensional form descriptor of rocks somehow improved resistance to impact from LA than highly flat and elongated particles. Lastly, the distribution of pore space investigated by means of the saturation method mostly showed moderate (R = 0.50) to strong (R = 0.90) and positive correlations to LA and MD tests.

scholarly journals On the occurrence of the T-loop RNA folding motif in large RNA molecules

RNA ◽  
2003 ◽  
Vol 9 (6) ◽  
pp. 640-643 ◽  
Author(s):  
A. S. KRASILNIKOV
Keyword(s):  
Rna Folding ◽  
Rna Molecules

scholarly journals The impact of broadleaved woodland on water resources in lowland UK: II. Evaporation estimates from sensible heat flux measurements over beech woodland and grass on chalk sites in Hampshire

2005 ◽  
Vol 9 (6) ◽  
pp. 607-613 ◽  
Author(s):  
J. Roberts ◽  
P. Rosier ◽  
D. M. Smith
Keyword(s):  
Heat Flux ◽  
Energy Balance ◽  
Excellent Agreement ◽  
Sensible Heat Flux ◽  
Late Summer ◽  
Eddy Correlation ◽  
Sensible Heat ◽  
Flux Measurements ◽  
Shallow Soils ◽  
The Impact

Abstract. The impact on recharge to the Chalk aquifer of substitution of broadleaved woodland for pasture is a matter of concern in the UK. Hence, measurements of energy balance components were made above beech woodland and above pasture, both growing on shallow soils over chalk in Hampshire. Latent heat flux (evaporation) was calculated as the residual from these measurements of energy balances in which sensible heat flux was measured with an eddy correlation instrument that determined fast response vertical wind speeds and associated temperature changes. Assessment of wind turbulence statistics confirmed that the eddy correlation device performed satisfactorily in both wet and dry conditions. There was excellent agreement between forest transpiration measurements made by eddy correlation and stand level tree transpiration measured with sap flow devices. Over the period of the measurements, from March 1999 to late summer 2000, changes in soil water content were small and grassland evaporation and transpiration estimated from energy balance-eddy flux measurements were in excellent agreement with Penman estimates of potential evaporation. Over the 18-month measurement period, the cumulative difference between broadleaved woodland and grassland was small but evaporation from the grassland was 3% higher than that from the woodland. In the springs of 1999 and 2000, evaporation from the grassland was greater than that from the woodland. However, following leaf emergence in the woodland, the difference in cumulative evaporation diminished until the following spring.

Sign in / Sign up

Export Citation Format

Share Document