We also examined changes in the configurational entropy of the ligands and the binding site. The first-order estimates used here, which are based on the probability distribution functions of rotatable bonds, quantify changes in thermal motion on binding. We checked the convergence of these calculations by computing the first-order entropies for subsets of frames from the total simulation, and found that the final values were always within a standard deviation of the values estimated by the subsets, as detailed in Supporting Information Figures .