Combined ab initio quantum mechanical and molecular mechanical calculations have been widely used for modeling chemical reactions in complex systems such as enzymes, with most applications being based on the determination of a minimum energy path connecting the reactant through the transition state to the product in the enzyme environment. However, statistical mechanics sampling and reaction dynamics calculations with a combined ab initio quantum mechanical (QM) and molecular mechanical (MM) potential are still not feasible because of the computational costs associated mainly with the ab initio quantum mechanical calculations for the QM subsystem. To address this issue, a reaction path potential energy surface is developed here for statistical mechanics and dynamics simulation of chemical reactions in enzymes and other complex systems. The reaction path potential follows the ideas from the reaction path Hamiltonian of Miller, Handy and Adams for gas phase chemical reactions but is designed specifically for large systems that are described with combined ab initio quantum mechanical and molecular mechanical methods. The reaction path potential is an analytical energy expression of the combined quantum mechanical and molecular mechanical potential energy along the minimum energy path. An expansion around the minimum energy path is made in both the nuclear and the electronic degrees of freedom for the QM subsystem internal energy, while the energy of the subsystem described with MM remains unchanged from that in the combined quantum mechanical and molecular mechanical expression and the electrostatic interaction between the QM and MM subsystems is described as the interaction of the MM charges with the QM charges. The QM charges are polarizable in response to the changes in both the MM and the QM degrees of freedom through a new response kernel developed in the present work. The input data for constructing the reaction path potential are energies, vibrational frequencies, and electron density response properties of the QM subsystem along the minimum energy path, all of which can be obtained from the combined quantum mechanical and molecular mechanical calculations. Once constructed, it costs much less for its evaluation. Thus, the reaction path potential provides a potential energy surface for rigorous statistical mechanics and reaction dynamics calculations of complex systems. As an example, the method is applied to the statistical mechanical calculations for the potential of mean force of the chemical reaction in triosephosphate isomerase. (C) 2004 American Institute of Physics.