Cations and hydration in catalytic RNA: Molecular dynamics of the Hepatitis Delta Virus ribozyme

¹ Institute of Biophysics, Academy of Sciences of the Czech Republic
² Department of Chemistry, The University of Michigan
³ National Centre for Biomolecular Research
⁴ Center for Complex Molecular Systems and Biomolecules

^* To whom correspondence should be addressed. E-mail: sponer{at}ncbr.chemi.muni.cz.

Submitted on December 7, 2005
Revised on January 20, 2006
Accepted on 20 March 2006

	Abstract

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 (MD) 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 a 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.

Key Words: RNA cation binding, backbone dynamics, catalytic RNA, electrostatic potential, hydration, molecular dynamics simulations

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