Two residues that are not part of the orthosteric and allosteric sites were randomly selected from the surface residues of proteins. Among them, one was taken as the first center, and the residues around it with the same number as the residues in orthosteric pocket were selected as patch1; and the other residue was taken as the second center, and the residues around it with the same number as the residues in allosteric pocket were selected as patch2. Then we calculated the evolutionary coupling strength between patch1 and patch2. The process was repeated four times, and the mean and standard deviation of the evolutionary coupling strength were calculated. Finally, we compared the evolutionary coupling strength between patch1 and patch2 with that between orthosteric and allosteric sites by using the student’s t-test. If the p value was less than 0.05, we marked it with an asterisk; if the p value was less than 0.01, we marked it with two asterisks.