  We extend the Effective Fragment Molecular Orbital (EFMO) method to the
frozen domain approach where only the geometry of an active part is optimized,
while the many-body polarization effects are considered for the whole system.
The new approach efficiently mapped out the entire reaction path of chorismate
mutase in less than four days using 80 cores on 20 nodes, where the whole
system containing 2398 atoms is treated in the ab initio fashion without using
any force fields. The reaction path is constructed automatically with the only
assumption of defining the reaction coordinate a priori. We determine the
reaction barrier of chorismate mutase to be $18.3\pm 3.5$ kcal mol$^{-1}$ for
MP2/cc-pVDZ and $19.3\pm 3.6$ for MP2/cc-pVTZ in an ONIOM approach using
EFMO-RHF/6-31G(d) for the high and low layers, respectively.
