Conformational Pathway for the Kissing Complex→Extended Dimer Transition of the SL1 Stem-Loop from Genomic HIV-1 RNA as Monitored by Targeted Molecular Dynamics Techniques

Aci, Samia; Mazier, Sonia; Genest, D.

doi:10.1016/j.jmb.2005.06.009

Cited by 22 publications

(17 citation statements)

References 52 publications

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“…This leads to formation of an intermediate in which base-pairs in the upper stem are proximate and poised to form both inter- and intra-molecular hydrogen bonding. Such an intermediate has previously been proposed (23) and recently visualized by molecular dynamics simulations in the context of short kissing SL1 dimers lacking the internal loop (25). The inclusion of the internal loop is expected to destabilize the upper stem making its base-pairs a key nucleation site for initiating the melting, exchange and reannealing of strands.…”

Section: Discussionmentioning

confidence: 81%

Resolving fast and slow motions in the internal loop containing stem-loop 1 of HIV-1 that are modulated by Mg2+ binding: role in the kissing–duplex structural transition

Sun

Zhang

Al‐Hashimi

2007

Nucleic Acids Research

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Stem loop 1 (SL1) is a highly conserved hairpin in the 5′-leader of the human immunodeficiency virus type I that forms a metastable kissing dimer that is converted during viral maturation into a stable duplex with the aid of the nucleocapsid (NC) protein. SL1 contains a highly conserved internal loop that promotes the kissing–duplex transition by a mechanism that remains poorly understood. Using NMR, we characterized internal motions induced by the internal loop in an SL1 monomer that may promote the kissing–duplex transition. This includes micro-to-millisecond secondary structural transitions that cause partial melting of three base-pairs above the internal loop making them key nucleation sites for exchanging strands and nanosecond rigid-body stem motions that can help bring strands into spatial register. We show that while Mg2+ binds to the internal loop and arrests these internal motions, it preserves and/or activates local mobility at internal loop residues G272 and G273 which are implicated in NC binding. By stabilizing SL1 without compromising the accessibility of G272 and G273 for NC binding, Mg2+ may increase the dependence of the kissing–duplex transition on NC binding thus preventing spontaneous transitions from taking place and ensuring that viral RNA and protein maturation occur in concert.

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Section: Discussionmentioning

confidence: 81%

Resolving fast and slow motions in the internal loop containing stem-loop 1 of HIV-1 that are modulated by Mg2+ binding: role in the kissing–duplex structural transition

Sun

Zhang

Al‐Hashimi

2007

Nucleic Acids Research

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“…83, 84 In a concerted multi-step progression, the loop-loop helix of the KL complex is extended in both directions by gradually dissociating the stems' intramolecular pairs and by reconstituting them in intermolecular fashion to complete the ED structure. 17,26,85 In the absence of NC, one of the initial steps requires mobilizing the flanking purines from their relatively stable tuckedin conformations, 27, 32 which can be mediated for example by base protonation. 86 In the same direction, NC binding can prevent the participation of these nucleotides in junction stabilization by constraining them into the bulged-out conformation observed in the crystal structures of the kissing conformer (Figure 7a).…”

Section: Implications Of Nc-hinge Interactions On the Isomerization Mmentioning

confidence: 99%

Understanding the Isomerization of the HIV-1 Dimerization Initiation Domain by the Nucleocapsid Protein

Turner

Hagan

Fabris

2007

Journal of Molecular Biology

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The specific binding of HIV-1 nucleocapsid (NC) to the hinge region of the kissing-loop (KL) dimer formed by stemloop 1 (SL1) can have significant consequences on its ability to isomerize into the corresponding extended duplex (ED) form. The binding determinants and the effects on the isomerization process were investigated in vitro by a concerted strategy involving ad hoc RNA mutants and electrospray ionization-Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry, which enabled us to characterize the stoichiometry and conformational state of all possible protein-RNA and RNA-RNA assemblies present simultaneously in solution. For the first time, NC-hinge interactions were observed in constructs including at least one unpaired guanine at the 5′-end of the loop-loop duplex, whereas no interactions were detected when the unpaired guanine was placed at its 3′-end. This binding mode is supported by the presence of a grip-like motif described by recent crystal structures, which is formed by the 5′-purines of both hairpins held together by mutual stacking interactions. Using tandem mass spectrometry, hinge interactions were clearly shown to reduce the efficiency of KL/ED isomerization without inducing its complete block. This outcome is consistent with the partial stabilization of the extra-helical grip by the bound protein, which can hamper the purine components from parting ways and initiate the strand exchange process. These findings confirm that the broad binding and chaperone activities of NC induce unique effects that are clearly dependent on the structural context of the cognate nucleic acid substrate. For this reason, the presence of multiple binding sites on the different forms assumed by SL1 can produce seemingly contrasting effects that contribute to a fine modulation of the two-step process of RNA dimerization and isomerization.

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“…Though the AMBER PARM94 force field is the most documented for nucleic acids, 40 a high propensity for helical protein structure is intrinsic in this force field and this limitation has been already reported 41,42 and corrected in later AMBER force fields. Aside from this limitation, the data here reported show that once the protein is abandoned in the water solvent in structures influenced by the presence of the neighboring DNA, the information of the latter presence is slowly forgotten, as far as the secondary structure is concerned.…”

Section: H3 Histone N-terminal Tail and Linker Dnamentioning

confidence: 99%

Modeling H3 histone N‐terminal tail and linker DNA interactions

2006

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Molecular dynamics computer simulations were performed for the 25-residue N-terminal tail of the H3 histone protein in the proximity of a DNA segment of 10 base pairs (bp), representing a model for the linker DNA in chromatin. Several least biased configurations were used as initial configurations. The secondary structure content of the protein was increased by the presence of DNA close to it, but the locations of the secondary motifs were different for different initial orientations of the DNA grooves with respect to the protein. As a common feature to all simulations, the electrostatic attraction between negatively charged DNA and positively charged protein was screened by the water solvent and counterbalanced by the intrinsic compaction of the protein due to hydrophobic effects. The protein secondary structure limited the covering of DNA by the protein to 4-5 bp. The degree of compaction and charge density of the bound protein suggests a possible role of H3 tail in a nonspecific bending and plasticity of the linker DNA when the protein is located in the crowded dense chromatin.

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Conformational Pathway for the Kissing Complex→Extended Dimer Transition of the SL1 Stem-Loop from Genomic HIV-1 RNA as Monitored by Targeted Molecular Dynamics Techniques

Cited by 22 publications

References 52 publications

Resolving fast and slow motions in the internal loop containing stem-loop 1 of HIV-1 that are modulated by Mg2+ binding: role in the kissing–duplex structural transition

Resolving fast and slow motions in the internal loop containing stem-loop 1 of HIV-1 that are modulated by Mg2+ binding: role in the kissing–duplex structural transition

Understanding the Isomerization of the HIV-1 Dimerization Initiation Domain by the Nucleocapsid Protein

Modeling H3 histone N‐terminal tail and linker DNA interactions

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