A magic methyl effect in the active site of a methyltransferase ribozyme
TL;DR
This work pinpointed how 2’-O-methylation of active site nucleotides synergistically enhance ribozyme activity by reducing ribose rings’ conformational flexibility by reducing ribose rings’ conformational flexibility.
Abstract
The chemical richness of RNAs is greatly enhanced by post-transcriptional modifications with RNA methylation as the most prominent type. RNA modifications modulate the stability, folding and interaction pattern of RNA molecules. Furthermore, emerging data suggests RNA modifications also directly regulate the activity of catalytic RNA molecules, i.e., ribozymes. Here, we employ classical and hybrid quantum-classical (QM/MM) molecular dynamics (MD) simulations to investigate the reaction mechanism of an artificial methyltransferase ribozyme MTR1. Importantly, we pinpoint how 2’-O-methylations of active site nucleotides synergistically enhance ribozyme activity by reducing the conformational flexibility of the ribose rings and rigidifying the active site. Finally, the herein reported crystal structure of the modified MTR1, solved at 2.6 Å resolution, validates the results of our simulations. Taken together, our work supports the purported central role of modified RNA for early RNA catalysis and may guide rational design of more efficient ribozymes. Emerging data indicate RNA modifications are important regulators of ribozyme activity. Here, the authors show how 2’-O-methylation of active site nucleotides enhances catalytic activity by reducing ribose rings’ conformational flexibility.