  Hydrogen bond networks play vital roles in biological functions ranging from
protein folding to enzyme catalysis. Here we combine electronic structure
calculations and ab initio path integral molecular dynamics simulations, which
incorporate both nuclear and electronic quantum effects, to show why the
network of short hydrogen bonds in the active site of ketosteroid isomerase is
remarkably robust to mutations along the network and how this gives rise to
large local electric fields. We demonstrate that these properties arise from
the network's ability to respond to a perturbation by shifting proton positions
and redistributing electronic charge density. This flexibility leads to small
changes in properties such as the partial ionization of residues and $pK_a$
isotope effects upon mutation of the residues, consistent with recent
experiments. This proton flexibility is further enhanced when an extended
hydrogen bond network forms in the presence of an intermediate analog, which
allows us to explain the chemical origins of the large electric fields in the
enzyme's active site observed in recent experiments.
