Monovalent ions modulate the flux through multiple folding pathways of an RNA pseudoknot

Roca, Jorjethe; Hori, Naoto; Baral, Saroj; Velmurugu, Yogambigai; Narayanan, Ranjani; Narayanan, Prasanth; Thirumalai, D.; Ansari, Anjum

doi:10.1073/pnas.1717582115

Cited by 24 publications

(29 citation statements)

References 68 publications

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“…Changes in Viscosity alter the flux between parallel assembly of RNA It is well accepted that RNA in general, and PK in particular, fold by parallel pathways. 26,27,51 Recently, it was shown unambiguously that monovalent cations could change the flux to the folded state between the two pathways in the VPK pseudoknot. Surprisingly, we find here (see Figure 5) that Φ could be also altered by changing the viscosity for both the HP and the PK.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…The folding mechanisms of PKs are diverse, 25 and they often reach the native structure by parallel pathways. 26 The use of two RNA molecules with different folded states, with both HP and PK folding occurring by parallel pathways, allows us to examine many consequences of viscosity effects on their folding.…”

Section: Rna Moleculesmentioning

confidence: 99%

Frictional effects on RNA folding: Speed limit and Kramers turnover

Hori

Denesyuk

Thirumalai

2018

Preprint

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“…We choose a sequence that forms a hairpin (HP) with no tertiary interactions from the human telomerase (hTR) and an H-type BWYV pseudoknot (PK), which is a minimal RNA motif with tertiary interactions. The folding mechanisms of PKs are diverse [26], and they often reach the native structure by parallel pathways [27]. The use of two RNA molecules with different folded states, with both HP and PK folding occurring by parallel pathways, allows us to examine many consequences of viscosity effects on their folding.…”

Section: Rna Moleculesmentioning

confidence: 99%

“…In BWYV PK case, k F ∼ 1.9 ms −1 with HI, whereas k F ∼ 1.1 ms −1 without HI, leading to a factor of ∼1.7 increase, which is similar to the hTR HP case. Changes in Viscosity Alter the Flux between Parallel Assembly of RNA: It is well accepted that RNA in general and PK in particular fold by parallel pathways [26,27,52]. Recently, it was shown unambiguously that monovalent cations could change the flux to the folded state between the two pathways in the VPK pseudoknot.…”

Section: Effect Of Hydrodynamic Interactionsmentioning

confidence: 99%

Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover

2018

Self Cite

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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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“…[7][8][9] Metal ions renormalize the negative charge on the phosphate groups and decrease the persistence length of the RNA chain enabling the chain to collapse in the initial stages of folding. [10][11][12] Metal ions are also found to affect the rate of conformational rearrangements, [13][14][15] modify the kinetic free energy barriers, 16 participate in the formation of transition states, 17 alter the dominant folding pathways [18][19][20] and are shown to be intricately involved in the catalytic mechanism of RNAs such as ribozymes. [21][22][23] Mg 2+ is the most ubiquitous metal ion, which is bound to the RNA in crystal structures.…”

Section: Introductionmentioning

confidence: 99%

Mg²⁺Sensing by an RNA Fragment: Role of Mg²⁺Coordinated Water Molecules

Halder

Kumar

Valsson

et al. 2020

Preprint

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RNA molecules selectively bind to specific metal ions to populate their functional active states making it important to understand their source of ion selectivity. In large RNA systems, metal ions interact with the RNA at multiple locations making it difficult to decipher the precise role of ions in folding. To overcome this complexity, we studied the role of different metal ions (Mg 2+ , Ca 2+ and K + ) in the folding of a small RNA hairpin motif (5 -ucCAAAga-3 ) using unbiased all-atom molecular dynamics simulations. The advantage in studying this small system is that it requires specific binding of a single metal ion to fold to its native state. We find that even for this small RNA, the folding free energy surface (FES) is multidimensional as different metal ions present in the solution can simultaneously facilitate folding. The FES shows that specific binding of a metal ion is indispensable for its folding. We further show that in addition to the negatively charged phosphate groups, spatial organization of electronegative nucleobase atoms drive the site specific binding of the metal ion. Even though the binding site cannot discriminate between different metal ions, RNA folds efficiently only in Mg 2+ solution. We show that the rigid network of Mg 2+ coordinated water molecules facilitate the formation of important interactions in the transition state. The other metal ions such as K + and Ca 2+ cannot facilitate the formation of such interactions. These results allow us to hypothesize possible metal sensing mechanisms in large metallo-riboswitches and they also provide useful insights for the design of appropriate collective variables for studying large RNA molecules using enhanced sampling methods.

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Monovalent ions modulate the flux through multiple folding pathways of an RNA pseudoknot

Cited by 24 publications

References 68 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

Mg²⁺Sensing by an RNA Fragment: Role of Mg²⁺Coordinated Water Molecules

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Monovalent ions modulate the flux through multiple folding pathways of an RNA pseudoknot

Cited by 24 publications

References 68 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

Mg2+Sensing by an RNA Fragment: Role of Mg2+Coordinated Water Molecules

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Mg²⁺Sensing by an RNA Fragment: Role of Mg²⁺Coordinated Water Molecules