RNA hydration: three nanoseconds of multiple molecular dynamics simulations of the solvated tRNA Asp anticodon hairpin 1 1Edited by J. Karn

Auffinger, Pascal; Westhof, Éric

doi:10.1006/jmbi.1997.1022

Cited by 159 publications

(150 citation statements)

References 73 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…2B) is consistent with the relatively few interactions of the dsRBM to the phosphodiester backbone of dsRNA inferred from both biochemical (Bevilacqua and Cech 1996) and structural studies (Ryter and Schultz 1998). Finally, we note that partially compromised activation of PKR upon substitution of U with c in dsRNA-47 might be because the imino proton at the 5-position of c alters the structure or hydration patterns of the major groove (Auffinger and Westhof 1997).…”

Section: Discussionsupporting

confidence: 79%

Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner

Nallagatla¹,

Bevilacqua²

2008

RNA

125

124

View full text Add to dashboard Cite

The human interferon-induced protein kinase PKR is a key component of innate immunity, a process in which it senses pathogenic RNA. PKR consists of an N-terminal dsRNA-binding domain (dsRBD) and a C-terminal kinase domain. Upon binding long (>33 base pairs) stretches of pathogenic dsRNA, PKR undergoes autophosphorylation, which activates it to phosphorylate eIF2a, leading to inhibition of translation initiation. Many cellular and viral transcripts contain nucleoside modifications, and these could affect PKR activation. For example, a 59-triphosphate confers the ability of relatively unstructured transcripts to activate PKR. Effects of internal RNA modifications on PKR activation have not been reported. Herein, PKR activation by ssRNA and dsRNA containing internal nucleobase, sugar, and phosphodiester modifications is analyzed. We find that for 59-triphosphate-containing ssRNA, most base and sugar modifications abrogate activation, although 29-fluoro-modified ssRNA does not, indicative of a critical role for hydrogen bonding at the ribose sugar. In the case of dsRNA, a more limited set of nucleoside modifications affect PKR activation. Watson-Crick base-pairing is required for activation, and some minor groove modifications abrogate activation while major groove modifications have little effect. Surprisingly, GU wobble pairs also largely abrogate dsRNA-mediated activation when present at modest levels. Modifications to dsRNA that abrogate activation have no significant effect on dsRBD binding, allowing such RNAs to act as inhibitors and suggesting a nonequivalence of binding ability and activation. Overall, the findings indicate that nucleoside modifications and wobble pairing may serve to discriminate self-RNA and pathogenic RNA in innate immunity.

show abstract

Section: Discussionsupporting

confidence: 79%

Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner

Nallagatla¹,

Bevilacqua²

2008

RNA

125

124

View full text Add to dashboard Cite

show abstract

“…In short, these comparisons reveal two trustworthy signatures: one for the trans-Hoogsteen A/U and one for the sheared A/G pairs+ A trans-A/U Hoogsteen pair presents a reactive A-N1 with a protected A-N7 and the U-N3 reactive in semi-denaturing conditions+ A sheared A/G pair presents a reactive A-N1, with an A-N7 either protected in native or reactive in semi-denaturing conditions+ In the sheared A/G pair, both the N1 and N7 of the G are protected in the native state+ A similar pattern of chemical reactivity was observed for the tandem sheared A/G pairs in the conserved quartet of the SECIS element (Walczak et al+, 1996)+ Overall, the agreement between the X-ray structure and the chemical probing reactivities is adequate+ The main exception is the G residue (at both N1 and N7 positions) of sheared A/G pairs+ We suggest that the water and ion shell surrounding the sheared A/G pairs hinders the reactivity of guanine residues (see Fig+ 3)+ NMR of DNA fragments (Dennisov et al+, 1997) as well as molecular dynamics simulations of RNAs (Auffinger & Westhof, 1997) have shown that water molecules in some hydration sites reside for hundreds of picoseconds+ The diffusing reactive species could well interact with water molecules before the water molecules in direct contact with the G residues exchange with the bulk solvent, especially when the observed "bound water" presents a low B-factor (i+e+, a low temperature factor and thus a high occupancy and a long residence time)+ A well-documented example occurs with pseudouridines in tRNAs, whose second imino proton (N1) has a markedly reduced exchange rate with bulk solvent due to a water bridge to its 59-phosphate (Auffinger et al+, 1996;Auffinger & Westhof, 1998;Davis, 1998…”

Section: Watson-crick Positionsmentioning

confidence: 84%

The 5S rRNA loop E: Chemical probing and phylogenetic data versus crystal structure

Leontis

Westhof

1998

RNA

Self Cite

120

123

View full text Add to dashboard Cite

“…Another approach to the sampling problem is to exploit the increasing power of computers to perform molecular dynamics simulations that extend into the nanosecond timescale (Daggett & Levitt, 1993;van Gunsteren et al, 1995;Cheatham & Kollman, 1996). However, there have been suggestions that more effective sampling of the conformational space of proteins can be obtained from multiple short trajectories rather than a single, long trajectory (Elofsson & Nilsson, 1993;Straub et al, 1994) A multiple molecular dynamics simulation approach has been investigated by Auffinger et al (1995) and Auffinger and Westhof (1997) in studies of a terminally restrained loop fragment of tRNAASp. They report six independent 500 ps simulations that differ only in the initial velocities.…”

mentioning

confidence: 99%

Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin

1998

View full text Add to dashboard Cite

Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.

show abstract

RNA hydration: three nanoseconds of multiple molecular dynamics simulations of the solvated tRNA Asp anticodon hairpin 1 1Edited by J. Karn

Cited by 159 publications

References 73 publications

Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner

Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner

The 5S rRNA loop E: Chemical probing and phylogenetic data versus crystal structure

Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin

Contact Info

Product

Resources

About