-𝑇〈𝑆〉 = 2.17 kcal/mol eqn 12 for a total of -14.36 kcal/mol. The covalent in-bond energy change from eqn 2 is 7.17 kcal/mol. There are 2 additional rotatable bonds in the covalent coming from the thiodinate; the entropy is slightly more and the distribution in Figure less defined. The entropic contribution of the covalently bound Nirmatrelvir is 13% of the internal binding energy, and in the non-covalently bound molecule it is 15.3%.