Fig. 5.

The transit through the Leu-valve as characterized by metadynamics. a, b A 6HZM-like structure generated by a targeted MD simulation with two ATP molecules and a uric acid in Site 3 was subjected to metadynamics simulations. The resultant conformation was used in six metadynamics simulations with a reaction coordinate defined by the distance between the center of mass of Cα atoms of four amino acids (F439, T542 from both protomers, black sticks) and the center of mass of the uric acid molecule. Blue-green-yellow–red lines represent uric acid and correspond to increasing simulation time points. Uric acid passed through the Leu-valve (green sticks) in all simulations. Amino acids in the extracellular gate are labeled with violet. c Biasing energy accumulated until the time point, when the uric acid molecule passed the Leu-valve