Note: In this image of Nirmatrelvir bound to Mpro, the solvent accessible protein surface (SAS) is displayed. This has the advantage of clearly showing the binding cavity. However, in this image and in general there could be a hydrogen appearing to penetrate the surface. This is the case with Nirmatrelvir and Mpro in the nitrogen atoms 19, 36 farthest, nearest nitrogens from the trifluoromethyl group. These both are hydrogen bond donors (info on next page) with Mpro atoms 1315, 1112 in hydrophilic GLU 166, hydrophobic PHE 140. There is no structural clash or overlap, and this is common in ligandprotein Chimera images. Figure shows the ligand binding without the surface. This particular state of Nirmatrelvir is an outlier in the histogram of docking runs. First, it is the highest scoring conformer. Second, there are 11 out of these that scored rounded to either 70 or 71. That is a PLP score of 2 difference, 2 steps of discreet jumps at ~1 to 69, which is unusual and not typical of wiggle in conformations. This gap in states, although not blatant of a total 1/3 kCal, could be due to the molecular interaction modeling. There doesn't seem to be anything conformationally that would make this conformer to stick out from the bump at 67-69 in Figure .