A . This corresponds to a conformation with a single water molecule bridging those two groups (see Figure ). From our REST2 simulations, we estimate that this conformation could be almost as populated as the main one (see SI). Further, we found the existence of these distinct conformations of the active site structure to be correlated with the changes in interfacial contacts examined earlier (Figure ), as it is a change in the conformation of the RNA ends that brings A118 phosphate closer to the active site (Figure ). These distinct active site conformations are thus associated with different relative positioning of the residues (in particular Glu96 and A118) in the active site, which may favor distinct reaction mechanisms, as we will now further investigate.