However, distant sites also contribute to the thermodynamics of catalytic residues. This is achieved through a mechanism called energetic coupling, which is shaped by a continuous pathway of van der Waals interactions that ultimately influences residues at the binding site with similar efficiency as the thermodynamic hotspots [53, 54] . Indeed in such cases, evolutionary constraints are not placed on merely one amino acid in the binding pocket, but on two or more residues that can be shown to be statistically coupled in MSAs [54, 55] . In addition to contributions to binding, these principles also explain why the core of a domain structure will remain largely conserved, while at functionally related places residues can (rapidly) co-evolve with an overall neutral effect [56] . Of course, these aspects of co-evolution are also of practical consequence for structure prediction and rational drug design [43] .