Rational Control of Enzymatic Enantioselectivity through Solvation Thermodynamics

The enantioselectivity of cross-linked crystals of γ-chymotrypsin in the transesterification of the medicinally important compound methyl 3-hydroxy-2-phenylpropionate ( 1 ) with propanol has been examined in a variety of organic solvents. The ( k cat / K M ) S / k cat / K M ) R ratio in this enzymatic process can be forced to span a 20-fold range simply by switching from one solvent to another; in fact, while the enzyme strongly prefers the S -enantiomer of 1 in some solvents, the R -antipode is more reactive in others. These striking observations are quantitatively rationalized by accounting for the energetics of desolvation of S - 1 and R - 1 in the enzyme-bound transition states. In order to accomplish this, explicit rules have been established for the modeling and thermodynamic quantification of the partially desolvated substrate's transition state moieties.