Transition structure selectivity in enzyme catalysis: a QM/MM study of chorismate mutase

Two different transition structures (TSs) have been located and characteriz ed for the chorismate conversion, to prephenate in Bacillus subtilis choris mate mutase by means of hybrid quantum-mechanical/molecular-mechanical (QM/ MM) calculations. GRACE software. combined with an AM1/CHARMM24/TIP3P poten tial. has I,ern used involving full gradient relaxation of the position of ca. 3300 atoms. These TSs have been connected with their respective reactan ts and products by the intrinsic reaction coordinate (IRC) procedure carrie d out in the presence of the protein environment, thus obtaining for the fi rst time a realistic enzymatic reaction path for this reaction. Similar QM/ MM computational schemes have been applied to study the chemical reaction s olvated by ca. 500 water molecules. Comparison of these results together wi th pas phase calculations has allowed understanding of the catalytic effici ency of the protein. The enzyme stabilizes one of the TSs (TSOHout) by mean s of specific hydrogen bond interactions, while the other TS (TSOHin) is th e preferred one in vacuum and in water. The enzyme TS is effectively more p olarized but less dissociative than the corresponding solvent and gas phase TSs. Electrostatic stabilization and an intramolecular charge-transfer pro cess can explain this enzymatically induced change, Our theoretical results provide new information on an important enzymatic transformation and the k ey factors responsible for efficient selectivity are clarified.