A Molecular Dynamics Simulation Study Of The 9_25-11 Dnazyme

DNAzymes (catalytic DNA) have recently attracted increased research interest with an eye towards applications as therapeutic agents and biosensors, among others. Advantages over proteins include an increased resistance to hydrolysis and cost-effective production. Most DNAzymes recruit divalent metal ions as cofactors, however D.M. Perrin and coworkers have recently synthesised a M2+-independent, multiple turnover DNAzyme (Dz9(25)-11 by the inclusion of two kinds of modified nucleotides (8-histaminyl-dA and aminoallyl-dU in place of dA and dT, respectively) which afford enhanced catalytic rates that are attributed to the roles of electrostatic (cationic amine) catalysis as well as both general base and general acid catalysis (imidazoles). In this regard, Dz9(25)-11 functions as a sequence specific RNaseA mimic. The use of DNAzymes in a number of applications notwithstanding, structural and dynamic information about DNAzymes in general is scarce compared to proteins. Moreover there is no X-ray structure of Dz9(25)-11, however, D.M. Perrin and coworkers have conducted a site-directed chemical study from which proximity information between specific nucleotides can be inferred. Here, this information is incorporated into an atomistic, fully solvated model of Dz9(25)-11using the GROMOS96 biomolecular simulation package. The structure, dynamics and putative function of the DNAzyme is discussed in light of the simulation results.