A. Warshel, Perspective on "The energetics of enzymatic reactions" - Warshel A (1978)Proc Natl Acad Sci USA 75 : 5250, THEOR CH AC, 103(3-4), 2000, pp. 337-339
The origin of the catalytic power of enzymes has been one of the most impor
tant open problems in molecular biology. Our early computer modeling studie
s [Warshel A, Levitt M (1976) J Mol Biol 103: 227 indicated that electrosta
tic effects give the largest contributions to enzyme catalysis; however, it
was not clear how enzymes can provide more electrostatic stabilization to
their transition states than water does. This fundamental problem has been
solved by the title paper. The paper pointed out that in reactions in water
the solvent must pay significant electrostatic energy for orienting its pe
rmanent dipoles toward the transition states. It was then demonstrated that
in enzymes the active site dipoles are already partially preoriented in th
e optimum direction and so much less electrostatic energy is lost in the re
organization process. It was further demonstrated that ion pairs and relate
d transition states are less stable in water than in preoriented dipolar en
vironments in general and in the active sites of real enzymes in particular
. Thus, it was concluded that enzymes stabilize their transition states by
preoriented dipoles and that the catalytic energy is already stored in the
preorientation of these dipoles during the folding process rather than in t
he enzyme substrate interaction.