To further understand how the V557L mutation could reduce the inhibitory effect exerted by Remdesivir on the transcription of SARS-CoV-2 RdRp 17 , we have performed MD simulations with V577L point mutation for the wildtype-RNA system (see SI Section 1.2 for details). We observed that UTP opposite to adenosine at +1 site can still maintain the catalytically active conformation upon V557L mutation (Fig. ). Intriguingly, we found that the Val-to-Leu mutation would re-orientate the side chain to the direction opposite to the translocation pathway (Fig. and). Specifically, the center of mass (c.o.m.) distance between the backbone/side chain of V557L and the base of upstream nucleotide (Fig. ) becomes obviously larger than that for V557 (Fig. ). This variation of the side chain orientation is observed not only in the wildtype-RNA system (Fig. and), but also happens when Remdesivir is embedded in the template strand (Fig. and). This observation has suggested that Remdesivir exerts no extra influence and the bulkier side chain upon V557L mutation would spontaneously rotate to leave sufficient space along the translocation pathway.