Homology modeling was used to analyze structure interactions between potential substrates and MsrA (see detail in supplementary methods). In previous studies, it has been shown that in the first step of MsrA‐catalytic oxidation, a sulfenic acid residue on Cys72 of MsrA forms by ROS attacking (MsrA‐CYO). Thus, we analyzed the orientation of different MsrA substrates in the active site of MsrA‐CYO (Fig. S1A–F). We found DMS adopts a preferred orientation with the distance of O‐S 3.8 Å (Table S1). In the presence of DMS binding, the distances of donor and acceptor atoms (D‐H···A) between the O atom from CYO72, the H atom from Tyr103‐OH, and Glu115‐COOH were 3.6 and 1.6 Å, respectively. Another question is whether the preferred orientation of DMS in the active site formed easily. Thus, energy barrier was used to evaluate the difficulty of orientation. Steering molecular dynamics (SMD) can operate single molecules to move closer or apart just like the working mode of atomic force microscopy. For oxidative reaction catalyzed by MsrA, substrates including DMS were pulled 16 Å away from MsrA and then pulled to the active site of MsrA. Curves of works showed how much energy was required to pull substrates to the active site as close as possible (Fig. S2A,B). It was obvious that much less energy was required for pulling DMS than Met substrates, indicating that the formation of sulfonium intermediate on DMS occurs more easily. As shown in Fig. S2C, DMS fitted properly in the catalytic pocket of MsrA, which also indicated DMS was a dominant substrate of MsrA.