Department of Physics
Bridging the gap between theory and experiment to derive a detailed understanding of hammerhead ribozyme catalysis
Herein we summarize our progress toward the understanding of hammerhead ribozyme (HHR) catalysis through a multiscale simulation strategy. Simulation results collectively paint a picture of HHR catalysis: HHR first folds to form an electronegative active site pocket to recruit a threshold occupation of cationic charges, either a Mg2 + ion or multiple monovalent cations. Catalytically active conformations that have good in-line fitness are supported by specific metal ion coordination patterns that involve either a bridging Mg2 + ion or multiple Na+ ions, one of which is also in a bridging coordination pattern. In the case of a single Mg2 + ion bound in the active site, the Mg2 + ion undergoes a migration that is coupled with deprotonation of the nucleophile (C17:O2'). As the reaction proceeds, the Mg2 + ion stabilizes the accumulating charge of the leaving group and significantly increases the general acid ability of G8:O2'. Further computational mutagenesis simulations suggest that the disruptions due to mutations may severely impact HHR catalysis at different stages of the reaction. Catalytic mechanisms supported by the simulation results are consistent with available structural and biochemical experiments, and together they advance our understanding of HHR catalysis. © 2013 Elsevier Inc.
catalysis, combined QM/MM, enzyme, free energy, hammerhead ribozyme, mechanism, RNA, simulation
Source Publication Title
Soukup, Garrett A.
Progress in molecular biology and translational science
Lee, Tai-Sung, Kin-Yiu Wong, George M. Giambasu, and Darrin M. York. "Bridging the gap between theory and experiment to derive a detailed understanding of hammerhead ribozyme catalysis." Catalytic RNA 120 (2013): 25-91.