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Who Activates the Nucleophile in Ribozyme Catalysis? An Answer from the Splicing Mechanism of Group II Introns

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    Who Activates the Nucleophile in Ribozyme Catalysis? An Answer from the Splicing Mechanism of Group II Introns
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    † International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy
    ‡ Laboratory of Computational Chemistry and Biochemistry, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
    § CNR-IOM-Democritos National Simulation Center c/o SISSA, via Bonomea 265, 34136 Trieste, Italy
    *[email protected]
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    Cite this: J. Am. Chem. Soc. 2016, 138, 33, 10374–10377
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    https://doi.org/10.1021/jacs.6b01363
    Published June 16, 2016
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    Abstract

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    Group II introns are Mg2+-dependent ribozymes that are considered to be the evolutionary ancestors of the eukaryotic spliceosome, thus representing an ideal model system to understand the mechanism of conversion of premature messenger RNA (mRNA) into mature mRNA. Neither in splicing nor for self-cleaving ribozymes has the role of the two Mg2+ ions been established, and even the way the nucleophile is activated is still controversial. Here we employed hybrid quantum–classical QM(Car–Parrinello)/MM molecular dynamics simulations in combination with thermodynamic integration to characterize the molecular mechanism of the first and rate-determining step of the splicing process (i.e., the cleavage of the 5′-exon) catalyzed by group II intron ribozymes. Remarkably, our results show a new RNA-specific dissociative mechanism in which the bulk water accepts the nucleophile’s proton during its attack on the scissile phosphate. The process occurs in a single step with no Mg2+ ion activating the nucleophile, at odds with nucleases enzymes. We suggest that the novel reaction path elucidated here might be an evolutionary ancestor of the more efficient two-metal-ion mechanism found in enzymes.

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    • Computational details of the calculations and Figures S1–S11 (PDF)

    • Movie S1 showing the GIIR structure (AVI)

    • Movie S2 showing the mechanism (AVI)

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    Cite this: J. Am. Chem. Soc. 2016, 138, 33, 10374–10377
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    https://doi.org/10.1021/jacs.6b01363
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