“…Distal residues can have a variety of effects on the structure [Chalissery et al, 2007;Chaptal et al, 2007], substrate binding affinity [Heitman et al, 2006;Carpten et al, 2007;Chalissery et al, 2007;Mirza et al, 2007], stability [Hong et al, 2007], and function [El Omari et al, 2006;Dupre et al, 2007;Klyuyeva et al, 2008] of a wide variety of different enzymes [Lee et al, 2011]. The semantics of defining the ''shell'' to which a specific amino acid residue belongs can be challenging, in particular in enzymes with large substrates, such as DNA polymerases.…”