Amongst the five prototypical small, self-cleaving ribozymes, the hepatitis delta virus ribozyme (HDV) stands out for its vastly superior catalytic rate and as the only viral ribozyme known to be associated with human infection. This makes HDV an excellent candidate for an archetypal RNA enzyme and has led to extensive experimental investigation of its properties. Unfortunately, this broad effort has given rise to a large amount of experimental data with various conflicting interpretations. At its core, the controversy revolves around an inability to unambiguously assign the roles of specific chemical actors implicated by structural data from X-Ray/Raman crystallography as well as mutational and biochemical studies. Here we present multidimensional free energy surfaces from QM/MM replica exchange umbrella sampling simulations that directly test multiple catalytic conformations suggested by prior experimentation and computation. The results allow for evaluation of competing mechanistic pathways as well as direct comparison with several experimental observables.

Multidimensional QM/MM free energy surfaces of RNA catalysis in the hepatitis delta virus ribozyme from replica exchange umbrella sampling simulations

245th National Meeting (2013)

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