Fig. 5: MD simulations of SARS-CoV-2 Mpro in the reduced versus oxidized state (C145- C117 disulfide) and calculated dimer stabilities.
a Selected distances along the 600 ns MD trajectory of Mpro with the disulfide bridge C145-C117 formed on both monomers. After just a few nanoseconds, N28 is displaced from its interaction with the backbone carbonyls of C145 and C117 through the amide moiety. It builds a hydrogen bond to the carbonyl of G146, with occasional interactions to the C117. Snapshots taken from MD trajectories illustrating the interactions of N28. In the reduced protein, N28 has stable interactions with the backbone atoms of C145 and C117 (b). Upon disulfide bridge formation (c), N28 is flipped and moves to interact with G146. d Summary of MMPBSA dimerization enthalpies for the different simulated variants of Mpro. Note the reduced dimerization enthalpies for Mpro containing the C145- C117 disulfide and after covalent binding of MAH to C145 in support of the experimental data. The effect is even clearer when considering the full linkage of the inhibitor (both to C145 and K137), whereby the dimerization process becomes endergonic.
