Evolutionary coupling range varies widely among enzymes depending on selection pressure

ABSTRACT Recent studies proposed that enzyme active sites induce evolutionary constraints at long distances. The physical origin of such long-range evolutionary coupling is unknown. Here, I use a recent biophysical model of evolution to study the relationship between physical and evolutionary couplings on a diverse data set of monomeric enzymes. I show that evolutionary coupling is not universally long-range. Rather, range varies widely among enzymes, from 2Å to 20Å. Furthermore, the evolutionary coupling range of an enzyme does not inform on the underlying physical coupling, which is short-range for all enzymes. Rather, evolutionary coupling range is determined by functional selection pressure. SIGNIFICANCE Until recently, only residues near enzyme active sites were thought to be evolutionarily constrained. However, recent studies proposed that active sites induce long-range evolutionary constraints. This seems to conflict with the common finding that physical couplings in proteins are short-range. This raises the question of how short-range physical couplings may cause long-range evolutionary couplings. Here, I show that the function that maps physical coupling into evolutionary coupling depends on functional selection pressure. Under weak selection, both couplings are similarly short-range; under strong selection, short-range physical coupling is non-linearly turned into long-range evolutionary coupling. Thus, due to a huge variation of selection pressure, evolutionary coupling range varies widely among enzymes, from very short (2 Å) to very long (20 Å).