Structural dynamics of precursor and product of the RNA enzyme from the hepatitis delta virus as revealed by molecular dynamics simulations
Language English Country Netherlands Media print
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
Grant support
GM62357
NIGMS NIH HHS - United States
Wellcome Trust - United Kingdom
PubMed
16045932
DOI
10.1016/j.jmb.2005.06.016
PII: S0022-2836(05)00666-2
Knihovny.cz E-resources
- MeSH
- Catalytic Domain MeSH
- Nucleic Acid Conformation MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Models, Molecular MeSH
- RNA Precursors chemistry genetics metabolism MeSH
- Protons MeSH
- RNA, Catalytic chemistry genetics metabolism MeSH
- RNA, Viral chemistry genetics metabolism MeSH
- Base Sequence MeSH
- Static Electricity MeSH
- Thermodynamics MeSH
- Hepatitis Delta Virus enzymology genetics MeSH
- Hydrogen Bonding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Names of Substances
- RNA Precursors MeSH
- Protons MeSH
- RNA, Catalytic MeSH
- RNA, Viral MeSH
The hepatitis delta virus (HDV) ribozyme is a self-cleaving RNA enzyme involved in the replication of a human pathogen, the hepatitis delta virus. Recent crystal structures of the precursor and product of self-cleavage, together with detailed kinetic analyses, have led to hypotheses on the catalytic strategies employed by the HDV ribozyme. We report molecular dynamics (MD) simulations (approximately 120 ns total simulation time) to test the plausibility that specific conformational rearrangements are involved in catalysis. Site-specific self-cleavage requires cytidine in position 75 (C75). A precursor simulation with unprotonated C75 reveals a rather weak dynamic binding of C75 in the catalytic pocket with spontaneous, transient formation of a H-bond between U-1(O2') and C75(N3). This H-bond would be required for C75 to act as the general base. Upon protonation in the precursor, C75H+ has a tendency to move towards its product location and establish a firm H-bonding network within the catalytic pocket. However, a C75H+(N3)-G1(O5') H-bond, which would be expected if C75 acted as a general acid catalyst, is not observed on the present simulation timescale. The adjacent loop L3 is relatively dynamic and may serve as a flexible structural element, possibly gated by the closing U20.G25 base-pair, to facilitate a conformational switch induced by a protonated C75H+. L3 also controls the electrostatic environment of the catalytic core, which in turn may modulate C75 base strength and metal ion binding. We find that a distant RNA tertiary interaction involving a protonated cytidine (C41) becomes unstable when left unprotonated, leading to disruptive conformational rearrangements adjacent to the catalytic core. A Na ion temporarily compensates for the loss of the protonated hydrogen bond, which is strikingly consistent with the experimentally observed synergy between low pH and high Na+ concentrations in mediating residual self-cleavage of the HDV ribozyme in the absence of divalents.
References provided by Crossref.org
RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview
The role of an active site Mg(2+) in HDV ribozyme self-cleavage: insights from QM/MM calculations
Disparate HDV ribozyme crystal structures represent intermediates on a rugged free-energy landscape
Molecular mechanism of preQ1 riboswitch action: a molecular dynamics study
Theoretical studies of RNA catalysis: hybrid QM/MM methods and their comparison with MD and QM
Cations and hydration in catalytic RNA: molecular dynamics of the hepatitis delta virus ribozyme
Molecular dynamics simulations of sarcin-ricin rRNA motif