Finally, the use of ensemble methods enabled us to discover the allosteric mechanism through which the binding of a ligand at the substrate binding site of 3CLPro is affected by binding of another ligand at an experimentally known allosteric binding site. We showed that the two binding sites are connected via a β-sheet strand that causes distortion to the cavity of the substrate binding site relative to its conformation in the absence of such an allosteric effect. Such a distortion of the main binding site has a negative impact on the process of dimerisation of the main protease which is essential for its activity. This explains the inhibitory effect of ligand binding at the allosteric binding site. We also discovered a novel mechanism of inhibition for a ligand hitherto only known to bind at the substrate binding site. We found that this ligand binds to an alternative binding site, blocking a key interdomain hydrogen bond leading to the rotation of domain III of the main protease and thereby preventing its dimerisation and hence catalytic activity. and funding from the UCL Provost. We acknowledge the United States Department of Energy (DOE) and Oak Ridge National Laboratory (ORNL) for providing access to and core hours on Summit (). We give particular thanks to Benjamin Aguirre Hernandez and Bronson Messer at ORNL for providing invaluable support, advice and special access to resources without which this work would not have been possible. Furthermore, we are grateful to all of the staff at ORNL and at the Hartree Centre for their generous support.