Nirmatrelvir is not a particularly strong non-covalent binder with average PLP score per atom of 2.0. This is seen in detail by the number of light colored blue atoms in Figure . However, upon inspection of Figure , notice that there are 4 separated anchor points in purple with adjacent red and the trifluoro group is red. The branching is not highly interacting but there are separated stably bound regions. Atoms C17, C18, N19, C20 are all near each other and score very high, also O38 and C41. N36 doesn't interact at all except for a small set of poses where the nitrogen has strong hydrogen bonding, and this is the case of the isolated binding pose score of 70, away from the bulk in the 1 st binding mode at 66-69. N19, N28, O38, N40 all are high scores, but not on the extreme side of ≥5 which would mean also buried and more interactive. In general the hydrogen bonding atoms are not the primary sources of Nirmatrelvir's score as can be seen by the high 4 to 5 contribution of various carbons and non-hydrogen bonded oxygens and nitrogen. Some potentially interacting nitrogens and oxygens are very weak, such as N9, O21, O27, N28, and N36. In particular, =O27 has no interaction which then allows it to be involved as ketone instigator in the covalent binding of Nirmatrelvir. Several of the ligand atoms given the location in either of hydro -phobic (nonpolar) or -philic (polar) neighborhoods and buried scores show good or bad placement with high or low scores.