The hepatitis delta virus (HDV) ribozyme is a self-cleaving RNA enzyme involved in the replication of a human pathogen, the hepatitis delta virus. Recent crystal structures of the precursor and product of self-cleavage, together with detailed kinetic analyses, have led to hypotheses on the catalytic strategies employed by the HDV ribozyme. We report molecular dynamics (MD) simulations (∼120 ns total simulation time) to test the plausibility of these hypotheses at atomic resolution. Site-specific self-cleavage requires a cytidine in position 75 (C75). A precursor simulation with unprotonated C75 reveals a rather weak dynamic binding of C75 in the catalytic pocket with spontaneous, transient formation of a H-bond between U-1(O2') and C75(N3). This H-bond is consistent with C75 acting as the general base. Upon protonation in the precursor, C75H⁺ moves towards its product location and establishes a firm H-bonding network within the catalytic pocket. However, a C75H⁺(N3)-G1(O5') H-bond, which would be expected if C75 acted as a general acid catalyst, was not observed on the present simulation timescale. The adjacent loop L3 may serve as a flexible structural element, possibly gated by the closing U20·G25 wobble base pair, to facilitate the conformational switch induced by a protonated C75H⁺. L3 also controls the electrostatic environment of the catalytic core, which in turn likely modulates C75 base strength and metal ion binding. We find that a distant RNA tertiary interaction involving a protonated cytidine (C41) is instable when unprotonated, leading to detrimental conformational rearrangements adjacent to the catalytic core.