The integration of structural and entropic features from conformational ensemble models will open up the use of a powerful lens to drive down ligand binding affinity and stabilize protein conformational states in design. Traditional drug design emphasizes optimizing the complementarity of a small molecule into the binding site. While this can improve enthalpy, it almost completely ignores entropy (except for consideration of the entropy gained by displaced solvent at the binding site). However, ligand properties, such as the number of hydrogen bonds, are associated with a difference in conformational entropy . Further, minor chemical changes can significantly affect entropies and affinities, as seen in the hTS case where a single methyl group difference leads to vastly different entropies . How minor changes to the ligand propagate to differences in protein conformational entropy remains a mystery (Figure ). Structural perturbations do not necessarily propagate through structure via a series of dramatic "domino" conformational changes from one binding site to distal site. Instead, distributed and non-linear changes throughout the ensemble lead to changes in distal dynamics (entropy) or changes in the dominant conformational state (enthalpy). Examining these through a free energy landscape perspective, any conformational changes modifies its free energy landscape and thus function, highlighting the need to combine, rather than isolate these features. Likewise, protein design, having been optimized for protein packing and stability, now faces the next frontier: designing improved binders and enzymes . While pre-paying entropic cost by establishing order in the ground state has been explored 90 , spatial entropic redistribution, achieved by increasing conformational entropy in functionally distal regions, is harder to design . Integrating structural and entropic changes from natural versus designed enzymes could lead to innovative ways to design functional proteins. Simultaneously, the conformational entropy of distal regions significantly differs between the two ligands. This leads the teal ligand to have significantly more conformational entropy in the distal region (represented by increased number of alternative conformations of distal residues), which could increase the teal ligand's binding affinity due to lower -TdS compared to the purple ligand. To use this prospectively, we need to understand the mechanism leading to increasing conformational entropy in distal regions.