This Article Full Text Full Text (PDF) Supplement All Versions of this Article: biophysj.105.079368v1 91/2/626    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krasovska, M. V. Articles by Sponer, J. Search for Related Content PubMed PubMed Citation Articles by Krasovska, M. V. Articles by Sponer, J.

Cations and Hydration in Catalytic RNA: Molecular Dynamics of the Hepatitis Delta Virus Ribozyme

Maryna V. Krasovska ^*, Jana Sefcikova , Kamila Réblová ^* , Bohdan Schneider , Nils G. Walter  and Jií poner ^*

^* Institute of Biophysics, Academy of Sciences of the Czech Republic, 61265 Brno, Czech Republic; Department of Chemistry, Single Molecule Analysis Group, The University of Michigan, Ann Arbor, Michigan 48109-1055; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic; and Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic

Correspondence: Address reprint requests to Jií poner, E-mail: sponer{at}ncbr.chemi.muni.cz; or Nils G. Walter, E-mail: nwalter{at}umich.edu.

The hepatitis delta virus (HDV) ribozyme is an RNA enzyme from the human pathogenic HDV. Cations play a crucial role in self-cleavage of the HDV ribozyme, by promoting both folding and chemistry. Experimental studies have revealed limited but intriguing details on the location and structural and catalytic functions of metal ions. Here, we analyze a total of 200 ns of explicit-solvent molecular dynamics simulations to provide a complementary atomistic view of the binding of monovalent and divalent cations as well as water molecules to reaction precursor and product forms of the HDV ribozyme. Our simulations find that an Mg²⁺ cation binds stably, by both inner- and outer-sphere contacts, to the electronegative catalytic pocket of the reaction precursor, in a position to potentially support chemistry. In contrast, protonation of the catalytically involved C75 in the precursor or artificial placement of this Mg²⁺ into the product structure result in its swift expulsion from the active site. These findings are consistent with a concerted reaction mechanism in which C75 and hydrated Mg²⁺ act as general base and acid, respectively. Monovalent cations bind to the active site and elsewhere assisted by structurally bridging long-residency water molecules, but are generally delocalized.

This article has been cited by other articles:

				A. L. Cerrone-Szakal, D. M. Chadalavada, B. L. Golden, and P. C. Bevilacqua Mechanistic characterization of the HDV genomic ribozyme: The cleavage site base pair plays a structural role in facilitating catalysis RNA, September 1, 2008; 14(9): 1746 - 1760. [Abstract] [Full Text] [PDF]

				J.-D. Beaudoin and J.-P. Perreault Potassium ions modulate a G-quadruplex-ribozyme's activity RNA, June 1, 2008; 14(6): 1018 - 1025. [Abstract] [Full Text] [PDF]

				K. Reblova, E. Fadrna, J. Sarzynska, T. Kulinski, P. Kulhanek, E. Ennifar, J. Koca, and J. Sponer Conformations of Flanking Bases in HIV-1 RNA DIS Kissing Complexes Studied by Molecular Dynamics Biophys. J., December 1, 2007; 93(11): 3932 - 3949. [Abstract] [Full Text] [PDF]

				R. Radhakrishnan Coupling of Fast and Slow Modes in the Reaction Pathway of the Minimal Hammerhead Ribozyme Cleavage Biophys. J., October 1, 2007; 93(7): 2391 - 2399. [Abstract] [Full Text] [PDF]

				C. Musselman, H. M. Al-Hashimi, and I. Andricioaei iRED Analysis of TAR RNA Reveals Motional Coupling, Long-Range Correlations, and a Dynamical Hinge Biophys. J., July 15, 2007; 93(2): 411 - 422. [Abstract] [Full Text] [PDF]

				A. Perez, I. Marchan, D. Svozil, J. Sponer, T. E. Cheatham III, C. A. Laughton, and M. Orozco Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of {alpha}/{gamma} Conformers Biophys. J., June 1, 2007; 92(11): 3817 - 3829. [Abstract] [Full Text] [PDF]

				C. Reymond, J. Ouellet, M. Bisaillon, and J.-P. Perreault Examination of the folding pathway of the antigenomic hepatitis delta virus ribozyme reveals key interactions of the L3 loop RNA, January 1, 2007; 13(1): 44 - 54. [Abstract] [Full Text] [PDF]

				P. L. Freddolino, M. Dittrich, and K. Schulten Dynamic Switching Mechanisms in LOV1 and LOV2 Domains of Plant Phototropins Biophys. J., November 15, 2006; 91(10): 3630 - 3639. [Abstract] [Full Text] [PDF]