Salt Effects on the Thermodynamics of a Frameshifting RNA Pseudoknot under Tension

Hori, Naoto; Denesyuk, Natalia A.; Thirumalai, D.

doi:10.1016/j.jmb.2016.06.002

Cited by 27 publications

(32 citation statements)

References 61 publications

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“…The heat capacities have two distinct peaks, which indicate there is at least one intermediate between the unfolded and folded states. This finding is consistent with previous experimental and simulation studies [28,48,49]. From the position of the peaks, we determined the two melting temperatures, T m1 and T m2 , whose values are listed in Table I.…”

Section: Resultssupporting

confidence: 90%

Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover

2018

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We investigated frictional effects on the folding rates of a human telomerase hairpin (hTR HP) and H-type pseudoknot from the Beet Western Yellow Virus (BWYV PK) using simulations of the Three Interaction Site (TIS) model for RNA. The heat capacity from TIS model simulations, calculated using temperature replica exchange simulations, reproduces nearly quantitatively the available experimental data for the hTR HP. The corresponding results for BWYV PK serve as predictions. We calculated the folding rates ( k) from more than 100 folding trajectories for each value of the solvent viscosity (η) at a fixed salt concentration of 200 mM. By using the theoretical estimate (∝ √N where N is the number of nucleotides) for folding free energy barrier, k data for both the RNAs are quantitatively fit using one-dimensional Kramers's theory with two parameters specifying the curvatures in the unfolded basin and the barrier top. In the high-friction regime (η ≳ 10 Pa·s), for both HP and PK, k values decrease as 1/η, whereas in the low friction regime, k values increase as η increases, leading to a maximum folding rate at a moderate viscosity (∼10 Pa·s), which is the Kramers turnover. From the fits, we find that the speed limit to RNA folding at water viscosity is between 1 and 4 μs, which is in accord with our previous theoretical prediction as well as results from several single molecule experiments. Both the RNA constructs fold by parallel pathways. Surprisingly, we find that the flux through the pathways could be altered by changing solvent viscosity, a prediction that is more easily testable in RNA than in proteins.

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Section: Resultssupporting

confidence: 90%

Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover

2018

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“…48,49 Our previous study also showed that the thermal and mechanical (un)folding occur predominantly through the I1 state. 47 The present results show that I1 state is not only thermodynamically stable, but also is the major kinetic intermediate.…”

Section: Resultssupporting

confidence: 54%

“…This finding is consistent with previous experimental and simulation studies. 27,46,47 From the position of the peaks, we determined the two melting temperatures, T m1 and T m2 , whose values are listed in Table 1. It should not go unnoticed that the melting temperatures, T m1 and T m2 , for the hTR HP are in excellent agreement with experiments, demonstrating the effectiveness of TIS model in predicting the thermodynamic properties of RNA.…”

Section: Resultsmentioning

confidence: 99%

Frictional effects on RNA folding: Speed limit and Kramers turnover

Hori

Denesyuk

Thirumalai

2018

Preprint

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We investigated frictional effects on the folding rates of a human Telomerase hairpin (hTR HP) and H-type pseudoknot from the Beet Western Yellow Virus (BWYV PK) using simulations of the Three Interaction Site (TIS) model for RNA. The heat capacity from TIS model simulations, calculated using temperature replica exchange simulations, reproduces nearly quantitatively the available experimental data for the hTR HP. The corresponding results for BWYV PK serve as predictions. We calculated the folding rates (k F s) from more than 100 folding trajectories for each value of the solvent viscosity (η) at a fixed salt concentration of 200 mM. Using the theoretical estimate (∝ √ N where N is number of nucleotides) for folding free energy barrier, k F data for both the RNAs are quantitatively fit using one dimensional Kramers' theory with two parameters specifying the curvatures in the unfolded basin and the barrier top. In the high-friction regime (η 10 −5 Pa·s), for both HP and PK, k F s decrease as 1 /η whereas in the low friction regime k F s increase as η increases, leading to a maximum folding rate at a moderate viscosity (∼ 10 −6 Pa·s), which is the Kramers turnover.From the fits, we find that the speed limit to RNA folding at water viscosity is between(1 − 4)µs, which is in accord with our previous theoretical prediction as well as results from several single molecule experiments. Both the RNA constructs fold by parallel pathways. Surprisingly, we find that the flux through the pathways could be altered by changing solvent viscosity, a prediction that is more easily testable in RNA than proteins.

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“…To arrive at an accurate model, which reliably predicts the thermodynamic properties of large RNA molecules, we first began with a sequence-dependent three-interaction site (TIS) coarse-grained (CG) model for nucleic acids (24), which has been adopted to study a range of problems related to RNA folding (2,10,(25)(26)(27)(28)(29)(30)(31)(32). Even with this simplification, the inclusion of both monovalent ions (present in excess concentration relative to divalent cations) and divalent ions explicitly is computationally demanding, although folding simulations of a 195-nt Azoarcus ribozyme and pseudoknots have been carried out successfully (10,33).…”

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confidence: 99%

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

Nguyên

Hori

Thirumalai

2019

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Salt Effects on the Thermodynamics of a Frameshifting RNA Pseudoknot under Tension

Cited by 27 publications

References 61 publications

Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover

Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover

Frictional effects on RNA folding: Speed limit and Kramers turnover

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

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