ArticleThe journal of physical chemistry. B2008
General base catalysis for cleavage by the active-site cytosine of the hepatitis delta virus ribozyme: QM/MM calculations establish chemical feasibility.
Article in The journal of physical chemistry. B, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 40 citations in OpenAlex.
- RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview.Chemical reviews · 2018Review
- Understanding in-line probing experiments by modeling cleavage of nonreactive RNA nucleotides.RNA (New York, N.Y.) · 2017Article
- A Two-Metal-Ion-Mediated Conformational Switching Pathway for HDV Ribozyme Activation.ACS catalysis · 2016Article
- Chemical feasibility of the general acid/base mechanism of glmS ribozyme self-cleavage.Biopolymers · 2015Article
- The role of an active site Mg(2+) in HDV ribozyme self-cleavage: insights from QM/MM calculations.Physical chemistry chemical physics : PCCP · 2015Article
- New tools provide a second look at HDV ribozyme structure, dynamics and cleavage.Nucleic acids research · 2014Article
- Quantum mechanical/molecular mechanical free energy simulations of the self-cleavage reaction in the hepatitis delta virus ribozyme.Journal of the American Chemical Society · 2014Article
- QM/MM studies of hairpin ribozyme self-cleavage suggest the feasibility of multiple competing reaction mechanisms.The journal of physical chemistry. B · 2011Article
- Quantum Mechanical/Molecular Mechanical Study of the HDV Ribozyme: Impact of the Catalytic Metal Ion on the Mechanism.The journal of physical chemistry letters · 2011Article
- Characterization of the Structure and Dynamics of the HDV Ribozyme at Different Stages Along the Reaction Path.The journal of physical chemistry letters · 2011Article
- Metal binding motif in the active site of the HDV ribozyme binds divalent and monovalent ions.Biochemistry · 2011Article
- Metal ions: supporting actors in the playbook of small ribozymes.Metal ions in life sciences · 2011Review
- The role of L1 stalk-tRNA interaction in the ribosome elongation cycle.Journal of molecular biology · 2010Article
- Hammerhead ribozymes: true metal or nucleobase catalysis? Where is the catalytic power from?Molecules (Basel, Switzerland) · 2010Article
- Protonation states of the key active site residues and structural dynamics of the glmS riboswitch as revealed by molecular dynamics.The journal of physical chemistry. B · 2010Article
- Extensive molecular dynamics simulations showing that canonical G8 and protonated A38H+ forms are most consistent with crystal structures of hairpin ribozyme.The journal of physical chemistry. B · 2010Article
- Molecular dynamics and quantum mechanics of RNA: conformational and chemical change we can believe in.Accounts of chemical research · 2010Article
- Theoretical studies of RNA catalysis: hybrid QM/MM methods and their comparison with MD and QM.Methods (San Diego, Calif.) · 2009Review
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Authors and funding
7 authors at 1 institution in 1 country.
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Abstract
The hepatitis delta virus (HDV) ribozyme is an RNA motif embedded in human pathogenic HDV RNA. Previous experimental studies have established that the active-site nucleotide C75 is essential for self-cleavage of the ribozyme, although its exact catalytic role in the process remains debated. Structural data from X-ray crystallography generally indicate that C75 acts as the general base that initiates catalysis by deprotonating the 2'-OH nucleophile at the cleavage site, while a hydrated magnesium ion likely protonates the 5'-oxygen leaving group. In contrast, some mechanistic studies support the role of C75 acting as general acid and thus being protonated before the reaction. We report combined quantum chemical/molecular mechanical calculations for the C75 general base pathway, utilizing the available structural data for the wild type HDV genomic ribozyme as a starting point. Several starting configurations differing in magnesium ion placement were considered and both one-dimensional and two-dimensional potential energy surface scans were used to explore plausible reaction paths. Our calculations show that C75 is readily capable of acting as the general base, in concert with the hydrated magnesium ion as the general acid. We identify a most likely position for the magnesium ion, which also suggests it acts as a Lewis acid. The calculated energy barrier of the proposed mechanism, approximately 20 kcal/mol, would lower the reaction barrier by approximately 15 kcal/mol compared with the uncatalyzed reaction and is in good agreement with experimental data.
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