Fig. 1. Schematic view of computational studies of enzyme catalysis. An initial guess for the transition state is introduced in a crystal structure of an enzyme ①, leading to a high-energy non-equilibrium structure ② that is optimized to ③, which is assumed to represent the transition state of the reaction. Conformational changes from ② to ③ are likely to occur on the μs timescale and extensive sampling on the coordinates perpendicular (blue) to the reaction coordinate (red) is needed for adequate description of the transition state ensemble.