In order to understand the large RMSD values for ARG298, we compare the first and the last MD snapshot of replica 9 of the 3CLPro-RQN-LZE system (see Figure ) which have very different RMSDs. Figure (left panel) compares the protein conformations in both these snapshots. It appears that domains I and II (residues 1 to 197) are still wellaligned in both conformations, although domain III has rotated (still keeping its intradomain conformation intact). This rotation leads to a substantial change in protein conformation and a corresponding large increase in ARG298 RMSD. This rotation is similar to the one experimentally reported to be triggered by R298A mutation. 84 ARG298 residue is known to play a key role in stabilising the relative position of N finger and domain III that is necessary for the dimerisation of the main protease. The formation of a hydrogen bond between the NH2 of ARG298 and the backhone oxygen of MET6 has such a stabilising effect (as shown by purple residues in Figure ). Incidentally, RQN binding to site A1 (as shown in the left as well as right panel of Figure ) requires the ligand to move in between the N finger and domain III that creates a gap between ARG298 and MET6 (as shown by yellow residues in Figure ). This leads to breaking of the hydrogen bond between these residues leaving domain III free to move causing the rotation as observed on mutating ARG to ALA experimentally. Such a rotation destabilises the interdomain structure of the main protease rendering it incapable of dimerising. It is well known that dimerisation is important for the catalytic activity of 3CL protease. Thus, we have discovered a novel mechanism of inhibition by RQN/MUT056399 without its binding to the substrate binding site.