To compare the ligand-residue contact frequency distributions, we perform the pairwise Kolmogorov-Smirnov (KS) test. The test compares the underlying continuous distributions F (x) and G(x) of two independent samples (in this case, two ligand-residue contact frequency distributions, each derived from separate MD trajectories and computed as described in section 3.3). Since the test is non-parametric, it is particularly suited to the comparison of ligand-residue contact frequency distributions as they have multiple peaks and are not normally distributed. To test the statistical certainty of two distributions being different from one another, we use the two sided p-test. For this test, the null hypothesis is that both of the distributions are sampled from the same underlying distribution. All KS tests are computed using the SciPy package in Python.