Short, strong (low barrier) hydrogen bonds occur when the pK values of the
atoms sharing the proton are similar. The overall distance is 2.5 Angstrom
or less, the deuterium fractionation factor is less than 0.5, the proton NM
R chemical shift can approach 20 ppm, and deuterium or tritium substitution
causes an upheld change in the chemical shift. Such bonds can have Delta H
values of 25 kcal/mol in the gas phase, and at least half that in water or
other high-dielectric medium. The strength of the hydrogen bond in an acti
ve site drops by similar to 1 kcal/mol for each pH unit mismatch in pKs, Wh
en a weak hydrogen bond in the initial enzyme-substrate complex is converte
d into a low-barrier one by alteration of the pK of the substrate or cataly
tic group so that the pKs match, the increase in hydrogen bond strength can
be used to help catalyze the reaction, A well-established example of this
is the reaction catalyzed by serine proteases. The pK of neutral histidine
is 14, while that of aspartate is similar to 6, Proton transfer from serine
to permit attack on bound substrate produces protonated histidine, with a
pK now matching that of aspartate, Studies with trifluoromethyl ketone inhi
bitors that form tetrahedral adducts show up to five orders of magnitude in
binding strength as the result of formation of a low-barrier hydrogen bond
between aspartate and histidine, Other enzymes whose mechanisms appear to
involve low-barrier hydrogen bonds include liver alcohol dehydrogenase, ste
roid isomerase, triose-P isomerase, aconitase, citrate synthase, and zinc p
roteases, It is likely that low-barrier hydrogen bonds form at the transiti
on state of any reaction involving general-acid or general-base catalysis,
as at that point the pKs of the catalytic group and reactant will be equal.
(C) 2000 Academic Press.