Conformational equilibrium of chorismate.: A QM/MM theoretical study combining statistical simulations and geometry optimisations in gas phase and in aqueous solution

We report a theoretical study on the conformational equilibrium of chorismate that precedes its rearrangement to prephenate, an important enzyme-catalyzed reaction. In first place we show that the usual classification of chorismate conformers based on the relative position of the hydroxyl and ether bridge, pseudo-diaxial and pseudo-diequatorial, is not the only relevant factor from the point of view of the a posteriori rearrangement. Here we also analyse another complementary geometrical classification based on the interatomic distance between the carbon atoms to be bounded. Using the umbrella sampling approach and this distance as distinguished internal reaction coordinate, the gas phase AM1 and in solution AM1/TIP3P potentials of mean force (PMF) for the transformation between short- and long-distances and pseudo-diaxial and pseudo-diequatorial conformers have been calculated. This procedure has allowed a wide conformational structures analysis of chorismate. From the free energy minima and maximum of the profile obtained in gas phase as a function of the interatomic distance, we located stationary structures on the potential energy surface. Due to the fact that the use of this coordinate as distinguished reaction coordinate to get the PMF in solution presents important histeresis problems, the dihedral angle describing the position of the ether bridge with respect to the ring has also been used with successful results, both in gas phase and in solution. To carry out this study of the equilibrium between pseudo-diaxial and pseudo-diequatorial conformers, we have used another dihedral angle that describes the relative position of the two substituents of the ring: the ether bridge and the hydroxyl group. Our theoretical results predict a relative population of pseudo-diaxial and pseudo-diequatorial chorismate conformers in aqueous solution that are in very good agreement with experimental data reported in the literature. (C) 2003 Elsevier B.V. All rights reserved.